Science topic

Drug Discovery - Science topic

The process of finding chemicals for potential therapeutic use.
Questions related to Drug Discovery
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I am here for specific answers or a list of investigation tools to determine the newly developed drugs/inhibitors/medicines.
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I am not actively participating in drug discovery processes anymore, however I would like to keep myself up-to date about industrial trends.
Scientists, researchers, anyone who is working/interested in Medicinal Chemistry related fields: What are the best resources to stay on track and follow scientific trends and news?
Thanks in advance for any suggestions that worked for you!
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I generally concur with everything mentioned so far. Expose yourself to trends and technologies. I highly recommend looking into Phenotypic Screening vs. target based screening.
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Are there certain precautions while preparing zinc fingers - containing proteins for MOLECULAR DYNAMICS SIMULATION?
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Hello,
As stated, simulation with metal centers can become a difficult endeavour. It all depends on your ultimate goal.
A rather "simple" approach is the use of positional restraints. Other methods use dummy atoms or additional parameters to improve the description (either geometric or electronic, but not both). A comprehensive description would also need of QM/MM methods.
I'm not a frequent user of GROMACS, but the AMBER documentation has several tutorials you could use as a starting point to gain some insight on the possibilities and choose based on your intended purpose for the simulation.
Hope this helps,
Regards
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I have prepared a drug library (energy minimized & conversion to PDBQT) in PyRx but while performing molecular docking in PyRx I am getting some false results. Can I run molecular docking in separate AutoDock Vina with PyRx prepared ligands?
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Yes, agreed with all
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For the molecular docking analysis using AutoDock Vina, how can I energy minimize hundreds of ligands in the ZINC15 drug library and also convert them to pdbqt?
Thank you very much!
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Of course, you can.
extract your minimized ligands from the working directory folder 'LIGANDS' and your protein in PDBQ format. For ease, put them in a same folder and create a box file.txt
you can then run docking on vina from .cmd or on autodock4.
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Hi . I was wondering if anyone could help me determine N terminal and C terminal end of a new peptide sequence that I'm looking to synthesise.
for e.g.
1. if DIEFRVLH is the peptide sequence I'm interested in, how can I determine the ends and directionality of these peptides?
2. What programs/softwares are available to study more characterstics of peptide and to determine its drug potential? I have already used ProtParam and Swiss ADME program.
Thank you
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David Salehi Thank you sir for your response to my question. I want to investigate the cytotoxicity of some paptides designed in silico on mamalian cell lines. So far, all I have are the sequences themselves and the purity. I used ProtParam and SwissADME to determine some physicochemical properties of these peptides such as Molecular weight, instability index.
I was looking for more information on peptides based on their sequences that would help me design the test. Do you have any recommendations on what I should keep in mind or look for while designing the test as it is my first time dealing with peptides?
Thank you for your paper. It helped me understand the concepts more.
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Dear Researchers
I am using Autodock-Vina for small molecule docking, I have a library of molecules around 400,000 and I have minimized ligands by MMFF94 and converted them into PDBQT file using Openbabel.
when I look into the pdbqt file number of active torsions are different from no of rotatable bonds.
In the following example number of active torsions are 9 and number of rotatable bonds for the same molecule is 11.
REMARK 9 active torsions:
REMARK status: ('A' for Active; 'I' for Inactive)
REMARK 1 A between atoms: C_1 and C_2
REMARK 2 A between atoms: C_2 and CA_3
REMARK 3 A between atoms: CA_3 and C_4
REMARK 4 A between atoms: CA_3 and N_6
REMARK 5 A between atoms: C_7 and C_9
REMARK 6 A between atoms: C_9 and O_10
REMARK 7 A between atoms: O_10 and C_11
REMARK 8 A between atoms: C_27 and C_29
REMARK 9 A between atoms: C_27 and C_30
Is it mandatory to have an equal number of active torsions are and the number of rotatable bonds?
Please let me know the way to specify the number of torsions in the ligand preparation (command line ).
Thank you
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during ligand preparation there is the the -Z and -I flags:
-Z inactivate all active torsions (default is leave all rotatable active except amide and guanidinium)"
[-I] string of bonds to inactivate composed of " print " of zero-based atom indices eg 5_13_2_10 " print " will inactivate atoms[5]-atoms[13] bond " print " and atoms[2]-atoms[10] bond " print " (default is not to inactivate any specific bonds)"
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Today, introducing a fluorine atom into a biologically active molecule seems to be a valuable approach in the process of drug discovery.
What are the most challenges problems faced by the chemistry of Fluorine in Drug discovery?
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Dear Alexander Sinko many thanks for sharing this very interesting technical qustion. Unlike some other RG members I will give you only one answer at the moment. First of all, I would not worry about the toxic and hazardous nature of elemental fluorine, as I assume that you are most likely not equipped to handle elemental fluorine anyway. The potential toxicity of fluorides does not present a big problem either because you are certainly not planning to eat your compounds, right? There are, however, some simple fluoro-organic compounds which are really toxic. The most (in)famous example is monofluoroacetic acid and its salts. Besides, many fluorinated precursors are commercially available and easy to handle. A very nice aspect of introducing fluorine atoms into biologically active molecules is that it adds another NMR-active nucleus (19F). Moreover, fluorine-substitution can also improve the solubility and volatility of organic molecules (the latter aspect is important for mass spectrometry).
In this sense I wish you good luck with your own work. Please stay safe and healthy! With best wishes, Frank Edelmann
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Hi all,
I have a number of proteins mainly from specific protozoans, Dictyostelium discoideum & humans. I need to find the active sites of each. I've used phyre2 to generate the structures and currently using Pymol to look at the structures.
I've tried using PDB files but unable to locate any, I've looked on unitprot to see the listed active sites and can't find any. I've followed a bunch of YouTube tutorials on how to find them with some wacky results. Online websites for pasting in the fasta file. No luck on any front and I'm completely out of ideas.
I'm towards the end of Mphil write up year, so my knowledge and experience with this is some what lacking.
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To predict / discover active site locations in proteins one has to do molecular docking studies.Pharmacy person will help you in this regards.
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Hi Everyone
I have calculated the effect of a drug on the inactivation of a protein at different temperatures using unpaired experiments. The drug has a significant effect (p<0.00001) on the function of the protein at all tested temperatures (12C, 25C and 37C). The temperature itself has an effect on the function of the protein. This data and many related experiments indicate the effect of the drug is strongest at 25C. However, I want to find a good statistical model to confirm that the effect of drug on the protein is temperature dependant and peaks at 25C. I was thinking about ANCOVA and Two way ANOVA but both do not seem to be intended to test a hypothesis like this.
Please note that none of the data sets are paired. These are all independent samples. And finding the optimum temperature for the drug effect is not my main aim. I want to confirm whether the temperature has an effect on the drug response
Has anyone encountered a problem like this before? What procedures did you take to properly test the hypothesis? Any recommendation/advice is most welcome
Thank you :)
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With the data you have, probably you want to keep the 2-way anova design with interaction, and then use the lsmeans or emmeans procedure appropriate for that model that your software provides to determine if groups (e.g. levels of the Temperature x Treatment interaction) are significantly different.
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Hello, I am intending to screen a library of compounds for an in vitro enzymatic assay. The target enzyme follows a Bi-Bi mechanism. The assay development phase is completed with kinetics parameters for both substrates are determined. I am looking into a rational approach to choose the concentration of both substrates and compounds to satisfy the following criteria:
-Inhibition Mechanism-blind design: the mode of inhibition and the substrate of which the inhibitor compete with is unknown.
-Minimize the concentration of the compounds to a reasonable concentration that still able to pick up any possible inhibitory mechanism.
Successful compounds will be used to identify Hits with dose response and IC50 later on.
Is there any recommendations/guideline followed in pharma to deal with this? is there any upper limit for a Hit to be accepted?
Thanks
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In my experience, the usual concentration of test compounds from a generic compound library used in high-throughput screening to search for enzyme inhibitors in an in vitro assay is 10 µM. For fragment libraries, a higher concentration, such as 100 µM may be used because the molecules are smaller and simpler, overall, than the molecules in generic screening libraries.
Going to higher compound concentrations may seem appealing, but the result is not necessarily better because you run into increasing problems with compound insolubility and interference with the assay readout as you increase the compound concentration.
As for the substrate concentrations, there is no "right" answer. There are trade-offs. Since you know the kinetic mechanism and the substrate kinetic parameters, you can calculate the ratio IC50/Ki using the appropriate Cheng-Prusoff relationship for inhibitors competitive with one substrate or the other as you vary the substrate concentrations. This ratio can be used as a measure of the sensitivity of the assay to find inhibitors. (For pure non-competitive inhibitors, the substrate concentrations don't affect the sensitivity.) I suggest you prepare a spreadsheet with columns for [A], [B] and IC50/Ki. Vary A and B and calculate IC50/Ki.
Typically, the lower you make one substrate concentration, the more sensitive the assay is for being inhibited by compounds competitive with that substrate (lower IC50/Ki), but the less sensitive it is for finding inhibitors competitive with the other. You can try to find a pair of substrate concentrations that achieve a balance.
To get around this issue, you could run two separate screens, if you can afford to, with one optimized for finding inhibitors competitive with A and the other optimized for finding inhibitors competitive with B.
You also have to consider the substrate concentrations needed to get a sufficient signal to run the screen successfully. Higher substrate concentrations allow a larger signal to be obtained while still under initial rate conditions, but higher substrate concentrations increase IC50/Ki. Cost and/or substrate availability may also have to be considered.
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I am trying to assess the potential for a set of small molecules to bind to transition metals (Cu2+, Zn2+, Fe2+, etc.), and am wondering if there is an established protocol for assessing binding constants.
One of the closer examples I have is the following paper (https://pubs.rsc.org/en/content/articlepdf/2006/cc/b611031b), in which the researchers test the absorbance spectra of a small molecule probe against ATP using a standard spectrophotometer. Would I then construct a concentration-response curve from a selected wavelength that shifts with a titration of metal?
I appreciate any and all help! Why is it that Beer's Law is popping in my head?
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If there is a change in the absorbance spectrum when the metal binds to the small molecule, you can use that to measure the affinity.
You should be careful to keep the pH constant, since some metal solutions can affect the pH.
When keeping the small molecule concentration constant and titrating the metal, you should subtract the spectrum of the metal alone from the spectrum of the mixture at each metal concentration. Better still, if possible choose a wavelength to monitor at which the metal has no absorbance.
Make sure all the absorbances are in the linear range of the spectrophotometer.
The concentration of the small molecule being monitored should be well below the Kd of the complex in order to get a good fit of the data to a Langmuir isotherm, which assumes that the free and total concentrations of the binding partner are essentially equal.
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Hello. I received a compound with molecular weight 453.292 and the only mass information for it is 1 micromol. This is very confusing because usually chemicals have a mass in grams or milligrams. I do not know how to calculate from this. I need to make up either 10mM or 1mM of the compound. Please can someone show me your calculation for either obtaining a final concentration of 10mM or 1mM (please show calculations for both, as i havent decided which one to make yet), how much DMSO I will need to use. Thank you
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I agree with dr.John Machell,it’s far a away from my speciality.
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Docking
software is easy to use and dock
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Dear Rajendran,
I agree with Rezvan, but if you still want an extension, you can request the company extend your licence and give you one month free.
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I am currently working in GPCR-ligand complexes. Is there any way or tool that I can use to know the protonation state of the ligand in the body? Schrodinger provides the protein preparation wizard that can help but it's not free. Please let me know of any free tools or ways to identify the protonation state of the ligand. Thanks
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Martin Klvana Ricardo J Ferreira Thanks I also find PROPKA helpful for predicting the pKa when the ligand is in the bound state.
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What web server, software or algorithm is suitable for clustering a large database of chemical compounds for drug discovery? (Free)
Thanks in advance for any guidance in this regard.
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Try RDKit python base module. Follow this https://www.macinchem.org/reviews/clustering/clustering.php
Best!!
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We are doing research in cancer drug discovery so can anyone suggest me a new Bio-info tool for drug screening.
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For Molecular Modeling you can try Marvin sketch or Chemsketch.
Molecular Docking: Maestro Schrödinger or Autodock
Virtual Screening : Maestro Schrödinger
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We have some good projects on bioinformatics. Interested researches having expertise in virtual screening/in silico drug discovery, GWAS, RNA seq, human genome analysis are requested to contact. We can jointly publish the articles.
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Please have look on our(Eminent Biosciences (EMBS)) collaborations.. and let me know if interested to associate with us
Our recent publications In collaborations with industries and academia in India and world wide.
EMBS publication In association with Universidad Tecnológica Metropolitana, Santiago, Chile. Publication Link: https://pubmed.ncbi.nlm.nih.gov/33397265/
EMBS publication In association with Moscow State University , Russia. Publication Link: https://pubmed.ncbi.nlm.nih.gov/32967475/
EMBS publication In association with Icahn Institute of Genomics and Multiscale Biology,, Mount Sinai Health System, Manhattan, NY, USA. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/29199918
EMBS publication In association with University of Missouri, St. Louis, MO, USA. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/30457050
EMBS publication In association with Virginia Commonwealth University, Richmond, Virginia, USA. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/27852211
EMBS publication In association with ICMR- NIN(National Institute of Nutrition), Hyderabad Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/23030611
EMBS publication In association with University of Minnesota Duluth, Duluth MN 55811 USA. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/27852211
EMBS publication In association with University of Yaounde I, PO Box 812, Yaoundé, Cameroon. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/30950335
EMBS publication In association with Federal University of Paraíba, João Pessoa, PB, Brazil. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/30693065
Eminent Biosciences(EMBS) and University of Yaoundé I, Yaoundé, Cameroon. Publication Link: https://pubmed.ncbi.nlm.nih.gov/31210847/
Eminent Biosciences(EMBS) and University of the Basque Country UPV/EHU, 48080, Leioa, Spain. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/27852204
Eminent Biosciences(EMBS) and King Saud University, Riyadh, Saudi Arabia. Publication Link: http://www.eurekaselect.com/135585
Eminent Biosciences(EMBS) and NIPER , Hyderabad, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/29053759
Eminent Biosciences(EMBS) and Alagappa University, Tamil Nadu, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/30950335
Eminent Biosciences(EMBS) and Jawaharlal Nehru Technological University, Hyderabad , India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/28472910
Eminent Biosciences(EMBS) and C.S.I.R – CRISAT, Karaikudi, Tamil Nadu, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/30237676
Eminent Biosciences(EMBS) and Karpagam academy of higher education, Eachinary, Coimbatore , Tamil Nadu, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/30237672
Eminent Biosciences(EMBS) and Ballets Olaeta Kalea, 4, 48014 Bilbao, Bizkaia, Spain. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/29199918
Eminent Biosciences(EMBS) and Hospital for Genetic Diseases, Osmania University, Hyderabad - 500 016, Telangana, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/28472910
Eminent Biosciences(EMBS) and School of Ocean Science and Technology, Kerala University of Fisheries and Ocean Studies, Panangad-682 506, Cochin, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/27964704
Eminent Biosciences(EMBS) and CODEWEL Nireekshana-ACET, Hyderabad, Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/26770024
Eminent Biosciences(EMBS) and Bharathiyar University, Coimbatore-641046, Tamilnadu, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/27919211
Eminent Biosciences(EMBS) and LPU University, Phagwara, Punjab, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/31030499
Eminent Biosciences(EMBS) and Department of Bioinformatics, Kerala University, Kerala. Publication Link: http://www.eurekaselect.com/135585
Eminent Biosciences(EMBS) and Gandhi Medical College and Osmania Medical College, Hyderabad 500 038, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/27450915
Eminent Biosciences(EMBS) and National College (Affiliated to Bharathidasan University), Tiruchirapalli, 620 001 Tamil Nadu, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/27266485
Eminent Biosciences(EMBS) and University of Calicut - 673635, Kerala, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/23030611
Eminent Biosciences(EMBS) and NIPER, Hyderabad, India. ) Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/29053759
Eminent Biosciences(EMBS) and King George's Medical University, (Erstwhile C.S.M. Medical University), Lucknow-226 003, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/25579575
Eminent Biosciences(EMBS) and School of Chemical & Biotechnology, SASTRA University, Thanjavur, India Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/25579569
Eminent Biosciences(EMBS) and Safi center for scientific research, Malappuram, Kerala, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/30237672
Eminent Biosciences(EMBS) and Dept of Genetics, Osmania University, Hyderabad Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/25248957
EMBS publication In association with Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Hyderabad Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/26229292
Sincerely,
Dr. Anuraj Nayarisseri
Principal Scientist & Director,
Eminent Biosciences.
Mob :+91 97522 95342
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Please have look on our(Eminent Biosciences (EMBS)) collaborations.. and let me know if interested to associate with us
Our recent publications In collaborations with industries and academia in India and world wide.
EMBS publication In association with Universidad Tecnológica Metropolitana, Santiago, Chile. Publication Link: https://pubmed.ncbi.nlm.nih.gov/33397265/
EMBS publication In association with Moscow State University , Russia. Publication Link: https://pubmed.ncbi.nlm.nih.gov/32967475/
EMBS publication In association with  Icahn Institute of Genomics and Multiscale Biology,, Mount Sinai Health System, Manhattan, NY, USA. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/29199918
EMBS publication In association with  University of Missouri, St. Louis, MO, USA. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/30457050
EMBS publication In association with  Virginia Commonwealth University, Richmond, Virginia, USA. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/27852211
EMBS publication In association with  ICMR- NIN(National Institute of Nutrition), Hyderabad Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/23030611
EMBS publication In association with  University of Minnesota Duluth, Duluth MN 55811 USA. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/27852211
EMBS publication In association with  University of Yaounde I, PO Box 812, Yaoundé, Cameroon. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/30950335
EMBS publication In association with  Federal University of Paraíba, João Pessoa, PB, Brazil. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/30693065
Eminent Biosciences(EMBS) and  University of Yaoundé I, Yaoundé, Cameroon. Publication Link: https://pubmed.ncbi.nlm.nih.gov/31210847/
Eminent Biosciences(EMBS) and  University of the Basque Country  UPV/EHU, 48080, Leioa, Spain. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/27852204
Eminent Biosciences(EMBS) and  King Saud University, Riyadh, Saudi Arabia. Publication Link: http://www.eurekaselect.com/135585
Eminent Biosciences(EMBS) and  NIPER , Hyderabad, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/29053759
Eminent Biosciences(EMBS) and  Alagappa University, Tamil Nadu, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/30950335
Eminent Biosciences(EMBS) and  Jawaharlal Nehru Technological University,  Hyderabad , India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/28472910
Eminent Biosciences(EMBS) and  C.S.I.R – CRISAT, Karaikudi, Tamil Nadu, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/30237676
Eminent Biosciences(EMBS) and  Karpagam academy of higher education, Eachinary, Coimbatore , Tamil Nadu, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/30237672
Eminent Biosciences(EMBS) and  Ballets Olaeta Kalea, 4, 48014 Bilbao, Bizkaia, Spain. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/29199918
Eminent Biosciences(EMBS) and  Hospital for Genetic Diseases, Osmania University, Hyderabad - 500 016, Telangana, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/28472910
Eminent Biosciences(EMBS) and  School of Ocean Science and Technology, Kerala University of Fisheries and Ocean Studies, Panangad-682 506, Cochin, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/27964704
Eminent Biosciences(EMBS) and  CODEWEL Nireekshana-ACET, Hyderabad, Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/26770024
Eminent Biosciences(EMBS) and  Bharathiyar University, Coimbatore-641046, Tamilnadu, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/27919211
Eminent Biosciences(EMBS) and  LPU University, Phagwara, Punjab, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/31030499
Eminent Biosciences(EMBS) and  Department of Bioinformatics, Kerala University, Kerala. Publication Link: http://www.eurekaselect.com/135585
Eminent Biosciences(EMBS) and  Gandhi Medical College and Osmania Medical College, Hyderabad 500 038, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/27450915
Eminent Biosciences(EMBS) and  National College (Affiliated to Bharathidasan University), Tiruchirapalli, 620 001 Tamil Nadu, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/27266485
Eminent Biosciences(EMBS) and  University of Calicut - 673635, Kerala, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/23030611
Eminent Biosciences(EMBS) and  NIPER, Hyderabad, India. ) Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/29053759
Eminent Biosciences(EMBS) and  King George's Medical University, (Erstwhile C.S.M. Medical University), Lucknow-226 003, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/25579575
Eminent Biosciences(EMBS) and  School of Chemical & Biotechnology, SASTRA University, Thanjavur, India Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/25579569
Eminent Biosciences(EMBS) and  Safi center for scientific research, Malappuram, Kerala, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/30237672
Eminent Biosciences(EMBS) and  Dept of Genetics, Osmania University, Hyderabad Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/25248957
EMBS publication In association with  Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Hyderabad Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/26229292
Sincerely,
Dr. Anuraj Nayarisseri
Principal Scientist & Director,
Eminent Biosciences.
Mob :+91 97522 95342
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We have some good projects on bioinformatics. Interested researches having expertise in virtual screening/in silico drug discovery, GWAS, RNA seq, human genome analysis are requested to contact. We can jointly publish the articles.
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Answer
Let me know if you are interested in collaborating with us.
Our recent publications In collaborations with industries and academia in India and world wide. Eminent Biosciences(EMBS) and Universidad Tecnológica Metropolitana, Santiago, Chile. Publication Link: https://pubmed.ncbi.nlm.nih.gov/33397265/ Eminent Biosciences(EMBS) and Moscow State University , Russia. Publication Link: https://pubmed.ncbi.nlm.nih.gov/32967475/ Eminent Biosciences(EMBS) and  Icahn Institute of Genomics and Multiscale Biology,, Mount Sinai Health System, Manhattan, NY, USA. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/29199918 Eminent Biosciences(EMBS) and  University of Missouri, St. Louis, MO, USA. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/30457050 Eminent Biosciences(EMBS) and  Virginia Commonwealth University, Richmond, Virginia, USA. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/27852211 Eminent Biosciences(EMBS) and  ICMR- NIN(National Institute of Nutrition), Hyderabad Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/23030611 Eminent Biosciences(EMBS) and  University of Minnesota Duluth, Duluth MN 55811 USA. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/27852211 Eminent Biosciences(EMBS) and  University of Yaounde I, PO Box 812, Yaoundé, Cameroon. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/30950335 Eminent Biosciences(EMBS) and  Federal University of Paraíba, João Pessoa, PB, Brazil. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/30693065 Eminent Biosciences(EMBS) and  University of Yaoundé I, Yaoundé, Cameroon. Publication Link: https://pubmed.ncbi.nlm.nih.gov/31210847/ Eminent Biosciences(EMBS) and  University of the Basque Country  UPV/EHU, 48080, Leioa, Spain. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/27852204 Eminent Biosciences(EMBS) and  King Saud University, Riyadh, Saudi Arabia. Publication Link: http://www.eurekaselect.com/135585 Eminent Biosciences(EMBS) and  NIPER , Hyderabad, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/29053759 Eminent Biosciences(EMBS) and  Alagappa University, Tamil Nadu, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/30950335 Eminent Biosciences(EMBS) and  Jawaharlal Nehru Technological University,  Hyderabad , India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/28472910 Eminent Biosciences(EMBS) and  C.S.I.R – CRISAT, Karaikudi, Tamil Nadu, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/30237676 Eminent Biosciences(EMBS) and  Karpagam academy of higher education, Eachinary, Coimbatore , Tamil Nadu, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/30237672 Eminent Biosciences(EMBS) and  Ballets Olaeta Kalea, 4, 48014 Bilbao, Bizkaia, Spain. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/29199918 Eminent Biosciences(EMBS) and  Hospital for Genetic Diseases, Osmania University, Hyderabad - 500 016, Telangana, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/28472910 Eminent Biosciences(EMBS) and  School of Ocean Science and Technology, Kerala University of Fisheries and Ocean Studies, Panangad-682 506, Cochin, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/27964704 Eminent Biosciences(EMBS) and  CODEWEL Nireekshana-ACET, Hyderabad, Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/26770024 Eminent Biosciences(EMBS) and  Bharathiyar University, Coimbatore-641046, Tamilnadu, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/27919211 Eminent Biosciences(EMBS) and  LPU University, Phagwara, Punjab, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/31030499 Eminent Biosciences(EMBS) and  Department of Bioinformatics, Kerala University, Kerala. Publication Link: http://www.eurekaselect.com/135585 Eminent Biosciences(EMBS) and  Gandhi Medical College and Osmania Medical College, Hyderabad 500 038, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/27450915 Eminent Biosciences(EMBS) and  National College (Affiliated to Bharathidasan University), Tiruchirapalli, 620 001 Tamil Nadu, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/27266485 Eminent Biosciences(EMBS) and  University of Calicut - 673635, Kerala, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/23030611 Eminent Biosciences(EMBS) and  NIPER, Hyderabad, India. ) Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/29053759 Eminent Biosciences(EMBS) and  King George's Medical University, (Erstwhile C.S.M. Medical University), Lucknow-226 003, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/25579575 Eminent Biosciences(EMBS) and  School of Chemical & Biotechnology, SASTRA University, Thanjavur, India Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/25579569 Eminent Biosciences(EMBS) and  Safi center for scientific research, Malappuram, Kerala, India. Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/30237672 Eminent Biosciences(EMBS) and  Dept of Genetics, Osmania University, Hyderabad Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/25248957 Eminent Biosciences(EMBS) and  Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Hyderabad Publication Link: https://www.ncbi.nlm.nih.gov/pubmed/26229292
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Does anyone have experience with PASS [1] for the use of predicting Bioactivities? I found an old paper [2], but I think it was commercialized and improved over the years. How would you judge the predictions made by the tool? Are they a good indicator? Is there something better out there?
[2] 10.1093/bioinformatics/16.8.747
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Dear Christoph,
First of all, you should know that PASS online is an internationally accredited webserver and considered one of the best and easiest bioinformatic tool to predict the bioactivity of a specific compound.
So, to learn how to use it correctly, i suggest you to carefully read this article (attached).
Best wishes
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Current commercially available implantable pumps are osmotic pumps (www.alzet.com) and programmable micro infusion pumps (www.iprecio.com) in the preclinical/drug discovery market. What would Users like to see in next generation commercially available pumps? (must have, nice to have, short term requirements, long term dream …… in this preclinical/drug discovery market –(non-clinical applications)
For inspiration – commercially available implantable clinical pumps.
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New and Important references on Implantable Pumps out in 2020 & 2021. One new book to come out in September 2021. Re-sharing Open Access Publication <Microdosing for drug delivery application—A review> Final Version. Sensors and Actuators A: Physical Volume 330, 15 October 2021, 112820 https://lnkd.in/gnvnwr5 A review of peristaltic micropumps Sensors and Actuators A: Physical, Volume 326, 1 August 2021, 112602 https://lnkd.in/gGh4ZSR Intelligent automated drug administration and therapy: future of healthcare. Drug Deliv. and Transl. Res. (2021). https://lnkd.in/gDKMUie Chapter 7 - Implantable drug delivery devices Drug Delivery Devices and Therapeutic Systems Developments in Biomedical Engineering and Bioelectronics 2021, Pages 129-156 https://lnkd.in/gw5RsTj Implantable Technologies: Peptides and Small Molecules Drug Delivery Editor: Ved Srivastava. https://lnkd.in/gTapPCS Royal Society of Chemistry. Copyright year 2022 Print ISBN           978-1-83916-222-0 Join Dr. Christian Schnell in his upcoming webinar on <Programmable pumps for compounds delivery in oncology research: implication for refinement and reduction of animal use.> https://bit.ly/3sWgYRh
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I want o start up my home-based Bioinformatic project on the immunological approach to post-covid complications.
or something related to probable drug discovery for covid complications.
Can anyone help me with ways or ideas in doing so?
If someone is already doing similar bioinformatic-based projects and need an apprentice, I am will to join as an apprentice.
I am a very hard working person please help.
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Is there any public patient RNAseq data repository related to COVID? If there is, and if they have FASTQs of them, any research may be done with those data by you at home. It may depend on the amount of meta-data connected to them, but you can search some relationship between some factors and some gene/gene set expressions.
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The contribution of natural products (NPs) to modern drug discovery can not be denied. More interestingly, the application of in silico (computer-based approaches) has even given more success to the search of NP-based starting molecules in the search for novel, potent and cheaper drug candidates. However, these in silico based methods also face some challenges. Obviously, most of the challenges are usually not discussed in scientific publications; in several cases rendering the use of in silico based approaches to investigate NPs (even in combination with experimental validation techniques) difficult to identify and propose new NP drug-base molecules. In this discussion, I would be happy if we can highlight some of these challenges. The idea is to give newcomers in this area of research an idea of what they can come across or should be expecting.
Peace
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See this article:
Applications of Virtual Screening in Bioprospecting: Facts, Shifts, and Perspectives to Explore the Chemo-Structural Diversity of Natural Products
10.3389/fchem.2021.662688
Here, we discuss some biases and limitations of computational methods applied in the screening of natural products.
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Search for discovery of new compounds is an ongoing process for drug discovery. Medicinal plants are a rich source of producing secondary metabolites. Normally natural products chemists prefer to isolate compounds from higher plants as compared to herbs.
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We have developed drug/co-former by co-crystal formation, in this case, we don't know how to distinguish the co crystal whether in really co-crystal formation or salt formation??
In solubility, both of them can increase the solubility of drug, meanwhile the thermal analysis (TGA and DSC) showed shifting higher of melting point peak (the melting point of drug is lower than that of co-former)
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one can also use XPS our recent paper
Cryst. Growth Des. 2021, 21, 735−747
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i have a crystal structure at the allosteric site but need to prove the worth of that allosteric site what experiments can be performed?
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The crystallization just let you know the binding site. As far as I know, to determine activity of each binding site, you should know the binding sequence, then mutation of each binding sequence=> check the activity of whole protein when you mutated it. By which, you know the function of binding sequence.
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I have a special interest in the hinge region for target-based drug discovery and want to know whether non-kinase targets have also hinge regions in thier ligand-binding pockets.
Could anybody give the answer about that?
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Many enzymes do: Check out the Database of molecular motions for other examples: http://www.molmovdb.org/cgi-bin/browse.cgi
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I am at the beginner level in drug design and drug discovery, and I am interested to learn more about this field. Which books are highly recommended to start from and gives me all essential concepts in medicinal chemistry?
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Good luck in this interesting field of pharmacy. Many books can be recommended, namely
1- An introduction to medicinal chemistry.
2- Burger's, Medicinal chemistry & drug design.
3- Fundamentals of medicinal chemistry.
4- Medicinal chemistry, the modern drug discovery process.
All the best for you
Regards
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To get ligands after submitting target protein (.pdb file)
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1. ADME-Tox filtering via the web server FAF-Drugs4 (http://fafdrugs4.mti.univ-paris-diderot.fr).
2. Docking-based virtual screening via the web server MTiOpenScreen (http://bioserv.rpbs.univ-paris-diderot.fr/services/MTiOpenScreen/), and
3. Molecular mechanics optimization to refine the docked complexes via the web server AMMOS2 (Automatic Molecular Mechanics Optimization for in silico Screening) (http://drugmod.rpbs.univ-paris-diderot.fr/ammosHome.php).
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I was invited to this conference organized by the Hazel pharmaceutical group in Prague 2021. I want to know if the event is real and if any other collage in the pharmacology/ drug discovery area has been invited. They have an official website with abstract submission and everything but i just want to make sure the event exist and is real in this time and place. Pleas give me feedbacks about it.
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thanks very much James Keane Bashkin I was thinking the same thing. This seems not a trustable event, not also a well stablished conference or website. I will definitely not go and specially during covid alert. Things like you are describing can happen, like a conference with 6 people and that king of things so i will not take that risk. Thanks again for your accurate response.
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AF2 may most strongly impact experimental determination of protein structure by multiple methods with possible benefits and negative impacts over time.
Some areas may need to quickly pivot or become obsolescent, whereas other may thrive.
Structures of large macromolecular machines should be enabled by having accurate computational structures for subunits and components.
The already great value of sequence data (which is doubling every 8 months) is likely to become far greater by being more directly connected to spatial information.
Overall the pace of biology and biophysical advances can be expected in increase by the ability to better harness the flood of sequence data.
What do you think?
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X-ray people might be impacted more than NMR and cryo-EM people by AF2. It may replace all biophysical techniques for structural determination someday, IMHO, they advertise much better than academic groups for the things they've achieved and still a long way to go (like when Rosetta first introduced). Not to mention the missing pieces like non-natural amino acids, binding partners, dynamics, different circumstances in the cell, more or less scientists would like to validate the prediction experimentally. However, it is hard to argue with its valuable inputs and insights before wet bench works that cost a lot.
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I have generated several .fit files for QSAR studies. I'd like go back and read, understand and extract some information from some of the .fit files I generated using Molecular Operating Enviroment (MOE) Software.
Is there a .fit file viewer or a published file format for this purpose?
I have attached herein a sample of the file.
Thanks in advance for every suggestion.
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If you have a technical question about antimicrobial research, there is a resource called REVIVE.
"REVIVE is working with leading experts in the field of antimicrobial R&D who are committed to support scientists from across the world in advancing their research. With this interface we want to help you to get in touch with these experts and to give you the opportunity to discuss your research questions with them."
REVIVE is a project of The Global Antibiotic Research & Development Partnership (GARDP). From the above paper:
"The Global Antibiotic Research & Development Partnership (GARDP; https://www.gardp.org) is a not-for-profit research and development (R&D) organization that addresses global public health needs by developing and delivering new or improved antibiotic treatments, while endeavouring to ensure that access to them is sustainable. Initiated by the WHO and the Drugs for Neglected Diseases initiative (DNDi), GARDP is an important element of the WHO’s Global Action Plan on Antimicrobial Resistance, which calls for new public–private partnerships to encourage research and development of new antimicrobial agents and diagnostics."
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Thank you for sharing such a nice information !
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I am running MD simulations for 10 ns only and I was wondering if this is good enough to analyze prospective drug candidates for 6M71.
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, , , And to thoroughly sample a microsecond timescale, the total simulation time must be at least three orders of magnitude longer.
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Many assays, including Cell-based assays, QPCR, some ELISA test, rely on the presence/absence of fluorescence. Diagnosis applications about cancer or antiobiotic resistance uses fluorescence ratio to draw a conclusion. All of these applications found a way around measuring the amount of fluorescence as reliable indicator of target potency. My question is exploratory, if we could reliably measure the value of the fluorescence of a cell, what application would be dramatically improved ?
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For fluorescence measurements you can use facs on which you can take fluorescence measurements at different wavelengths, can provide quantitative and qualitative data from cell surface receptors or intracellular molecules
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Reverse pharmacology and forward pharmacology are two approaches to drug discovery. I want to know the clear and simple difference and which is better among these.
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Reverse pharmacology : target-based drug discovery (TDD) is the science of integrating documented clinical/experiential hits, into leads by transdisciplinary exploratory studies and further developing these into drug candidates by experimental and clinical research.
Classical pharmacology, also known as forward pharmacology, or phenotypic drug discovery (PDD), relies on phenotypic screening (screening in intact cells or whole organisms) of chemical libraries of synthetic small molecules, natural products or extracts to identify substances that have a desirable therapeutic effect.
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Hello,
I have some problems with removing diphenyl phosphoryl azide (DPPA) from the reaction mixture. I am using DPPA to convert the acid carboxylic group to isocyanate, using toluene as a solvent of reaction. During the work-up, I use ethyl acetate to extract my product from the aqueous phase. In the next, I wash the organic phase with HCl 2.5%, H2O, and brine. Finally, I remove the solvent using the rotavapor. Does someone suggest another type of work-up?
My product is soluble on toluene, THF, dichloromethane, and ethyl acetate.
Best regards,
Sara Moura
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Frank T. Edelmann, I did not follow a literature procedure. Thanks for your solution, recrystallization.
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Could we think about drug molecules without small molecules? I mean less introduce foreign particles in our body.
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You can immobilize the drug in a stable reagent or maybe try for a probiotic drink, candy formulation or injection of saline/body fluids.
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Dear RG members
Heterocyclic moieties play a significant role in the drug discovery and development. Please, Can anyone provide the name of the currently-available drug (s) having a 1,3,4-oxadiazoline ring?
Regards
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There are some RG members such as you and Abdelkader BOUAZIZ can support me by answering my questions and providing advice privately. Other members can't do that, So, they may support me via recommendations even for the answers belong to my thanks' ones.
Regards
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Membrane proteins are very essential parts of the cell. They usually control the influx and efflux of materials. Determining the exact function i.e. exact mechanisms can be very helpful for research like drug discovery. Can computational methods aid in this process?
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1. Determine the primary structure.
2. Determine or predict the secondary, tertiary, and quaternary structure.
3. Search for functional information available for homologous structures.
4. Predict the function based on the available information.
5. Test the prediction computationally by exploring, both qualitatively and quantitatively, the functionally relevant bio(macro)molecular interactions.
6. Confirm the prediction experimentally.
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I will pass the topic to some colleagues in our faculty and will let you know if there were any positive replies. Good luck with your work!
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How are Artificial intelligence and Machine Learning boosting COVID-19 drug discovery process?
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See the link below, which is titled:
Overview of artificial intelligence in medicine
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We investigate the mechanisms of Parkinson's disease and do drug design for Parkinson's disease. We use theoretical physical chemistry, biophysics and bioinformatics in our studies. We are in need of experimental collaborators to apply for funding from the Michael J Fox foundationand COST EU projects. Are you interested? 
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Good answer dear Orkid Coskuner
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I just want to know the cells should be viewed under which filter.
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You can do ethidium bromide and acridine orange staining in 12 well-plates. The principal is the same. Just change the seeding cell number and stain volume.
Take a look at Ribbe et al. 2005 paper for complete protocol
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I am trying to synthesize a compound which has both carboxylic acid and amine. During the purification, when I do the pH adjustment it forms a zwitterion and goes into the aqueous layer. Is there a way to desalt such compounds?
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Crystallization of a zwitterion at the isoelectric point is tricky and often inefficient. If you only need a small amount of product and high yield is not the goal, AND you have a good estimate of pI, this can be the quickest way to get what you need. If you are doing this preparatively and/or if the compound does not crystallize well from your original mixture, ion exchange resins will probably be the most effective tools. (If you are trying to recover your product from a complex mixture, you will need to do IEX chromatography; please provide more details.)
When amino acid zwitterions are being synthesized, cation exchange resins such as Dowex 50, Amberlite IRC120 and others offer a very simple and efficient method for recovering products. The following process is frequently used following acid treatment, such as amino acid amide hydrolysis in HCl(aq):
RCH(NH[R'C=O])CO2H + xs HCl(aq) --> RCH(CO2H)NH3+ . Cl- + R'CO2H
The hydrolysis mixture consists of RCH(CO2H)NH3+ . Cl-, R'CO2H, water and excess HCl (e.g. R'=CH3 for an amino acid acetamide, where acetic acid is a volatile byproduct).
1) Evaporate excess volatile acid (rotary evaporation will remove water and HCl gas.) Purging HCl gas in a stream of N2(g) beforehand (fume hood) will reduce bumping during evaporation. Vent the vacuum pump exhaust to fume hood.
2) Dissolve the acid evaporation residue in a small volume of water
3) Calculate the number of millimoles of the zwitterionic substance you intend to isolate and pack a short column with 2-5 times this number of milli-equivalents of appropriately-washed NH4-form ion exchange resin (preparation usually done by washing with strong acid solution followed by water to give neutral eluate, then aqueous ammonia treatment to convert RSO3H groups to RSO3- .NH4+, and finally thorough washing with deionized water to give neutral filtrate.)
4) Slowly apply the solution of evaporated hydrolysis mixture residue onto the column, then wash the column with pure water until the eluate is free of Cl- (AgNO3 test) and the pH is neutral (or not lower than the pH of your DI water). At this point, the acidified zwitterion should be completely bound to the resin [RCH(CO2H)NH3+ . resin-SO3-]. (Check the column application eluate to be sure nothing has leaked through. TLC with ninhydrin detection works well for amino acids). You may also check dried drops of eluate with ninhydrin to be sure that displaced NH4+ ion is no longer eluting from the column.
Elute the washed column with aqueous NH4OH, using approximately twice the number of millimoles as meq of resin (e.g a column containing 50 mL of 0.8 meq/mL resin would be eluted with 2 x 50 x 0.8 = 80 mmol of NH4OH(aq), say 40 mL of 2 M). If the product has not completely eluted from the column by this time, more water should be used before you add more ammonia. Very hydrophobic amino acids may elute better if some methanol or ethanol is added to the water.
5) Evaporate the ammonia eluate. As with the HCl solution in step 1, this solution may behave better during rotary evaporation if you first bubble a stream of N2 gas into the eluate to purge excess NH3 (fume hood), followed by vacuum evaporation, only heating once all free ammonia is gone. Nearly all ammonium carboxylate salts (RCO2- . NH4+) decompose upon evaporation with heating to carboxylic acids, so this step is basically:
[RCH(CO2-)NH2 .NH4+](aq) --> RCH(CO2-)NH3+(s) + NH3(g)
i.e. once ammonia gas leaves, this residue is theoretically pure zwitterion.
6) At this point the purification method of choice is usually recrystallization, commonly from water-alcohol mixtures.
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I am looking to publish part of my medicinal chemistry project as a communication article. I am looking for journal impact around 5-6. Any suggestions?
Thanks.
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Medicinal chemistry ? Do you mean clinical chemistry? Main journals are Clinical Chemistry and Clin Chem Lab Medicine.
Maybe you need a pharmacological journal when your project is about new drugs.
I agree with Riaz Khan that you have to figure this out for yourself, start with looking for publications that are very similar to your work.
Besides, journals with impact factor 5-6 are very critical about added value and proven evidence of the work doen.
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For virtual screening, what area of the receptor should be selected as the search box for the binding site, if the area around the bound ligand in the pdb is far away from the catalytic triad in the receptor? I ran virtual screening in GOLD of pdb 3U1I, for which the bound ligand is the peptide of (BEZ)(NLE)KR(OAR), against a PPI library, and I had chosen my active site to be all the atoms within 12A of a particular oxygen atom in SER 135, since the catalytic triad in this protein is SER135, HIS51, and ASP75, even though the site the peptide ligand was bound to doesn't completely overlap with the active site area I selected. I also re-docked the peptide ligand during the virtual screening as well to make sure it still binded similarly, but I noticed that the predicted binding poses of the re-docked peptide ligand were all kind of different from the original peptide ligand in the pdb file.
I'm a little worried about the validity of my docking results and unsure if the highest ranked docked compounds from the PPI library from the VS I ran and their predicted binding poses are likely since I don't really understand if I choose a good active site. Should I re-run the VS and increase the search box to 15A or 20A around the catalytic triad so that the binding pose of the re-docked peptide ligand will match the actual pose of the peptide ligand in the pdb? But wouldn't that give more false positives in my docking results?
I thought it was important to keep the search box as small as possible, so I was actually thinking maybe my results would be more accurate if I made the active site to be 10A around the catalytic triad, but I'm not sure if my reasoning makes sense?
I think I read somewhere that it also depends on what types of ligands are involved, right? Because I think the Protein-Protein Interaction library has mostly small molecules, so I guess that's very different from the peptide ligand in the pdb 3U1I, right? Is that because peptide ligands are bigger than small molecules or are there other differences to be aware of how peptides bind compared to how small molecules bind to a receptor? What other types of ligands are there that I would need to consider in virtual screening, and how would it change how I set up my VS run? I've been reading so many papers on virtual screening, etc, but none of the papers I've read have discussed this kind of situation, so I'm really confused on if what I'm doing will lead to likely potential compounds that I could test in the wet lab for binding.
I'm very new to virtual screening and am still learning about chemistry and biochemistry, so I was just hoping someone could explain how to decide what to choose as the active site during VS in general, especially when the ligand from the pdb isn't bound near the expected catalytic triad area?
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This is totally up to you. If you would like your docking-based hits to have the same effect as the co-crystallized ligand (e.g., allosteric inhibitor), then use it as a reference for the binding site. If you wish docking hits to be substrate-competitive inhibitors, then use the enzyme's catalytic site to generate the docking grid.
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The global average surface temperature rose 0.6 to 0.9 degrees Celsius (1.1 to 1.6° F) between 1906 and 2005, and the rate of temperature increase has nearly been doubled in the last 50 years. Temperatures are certain to go up further and may lead to fast genetic mutations in some pathogenic microbes to become accustomed to the new climate and proliferate resistant gene distribution over geographies. In addition, the overuses of antibiotics is also triggering the issues at a great step. Near about 10 most deadly bacterial pathogens have already been registered as antibiotic-resistant. Mycobacterium tuberculosis is one of them, that has already been created a huge challenge to overcome in their own right and will only become harder to control as their resistance to antibiotics grows. The development of new antibiotics is slow and difficult work but bacterial resistance is decreasing our arsenal of existing drugs posing a catastrophic threat as ordinary infections become untreatable.
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Addressing the global shortage of, and access to, medicines and vaccines
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Bioavailability
1. The rate and extent of drug absorption of unchanged drug from its dosage form into the systemic circulation.
2. Measured by the demonstrated bioequivalence studies of reference protocol.
3. Bioavailability is a comparison of the drug product to an IV formulation.
4. This studies are expletory
5. Evaluate geometric ratio but don’t test a statistical hypothesis
6. Not require a similar time to achieve peak blood concentrations.
7. Provide indirect information regarding the pre-systemic and systemic metabolism of the drug
8. Determined only which active ingredient or moiety become available in the site of action.
9. Provide useful information to establish dosage regimens and to support drug labeling, such as distribution and elimination characteristics of the drug
10. For example, if 100 mg of a drug are administered orally and 70 mg of this drug are absorbed unchanged, the bioavailability is 0.7 or 70%
Bioequivalence
1. Two or more similar dosage forms reach the systemic circulation at the same relative rate and extent.
2. Bioequivalence has been established via bioavailability testing.
3. Bioequivalence is a comparison with predetermined bioequivalence limits.
4. This studies are confirmatory .
5. Test a statistical hypothesis by evaluating geometric ratio.
6. Require similar times to achieve peak blood concentrations.
7. Provide a link between the pivotal and early clinical trial formulation.
8. Determined the therapeutic equivalence between the pharmaceutical equivalence generic drug product and a corresponding reference listed drug.
9. Provide information on product quality and performance when there are changes in components, composition and method of manufacture after approval of the drug product.
10. Example- a receptor in the brain - the brand name and the generic drug should deliver the same amount of active ingredient to the target site.
Have any more specific or important point of these differences?
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I appreciate your answer Mr. Luiz Querino Caldas
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I am looking for databases that contain microRNA-drug interactions. Any suggestions or recommendations?
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Dear Ali Akbar Jamali ,
Look the link, maybe useful.
Regards,
Shafagat
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I am working on computationally understanding the active and inactive conformations of some proteins. Simulating the inactive conformation from the active conformation is reported in literature by performing enhanced sampling MD studies, like Metadynamics, REMD etc., in which energy is added in particular co-ordinates called collective variables. This makes it slightly biased.
If I run unbiased atomistic molecular dynamics simulations of several microseconds, will my protein explore the conformational space by crossing the energy barriers? Or will the system be eternally stuck in a local minimum which it first reaches?
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Hi Rajiv,
It depends on the system you are studyng, some systems dont show important conformational changes in the microsecond or even in the milisecond time scale not only because they get trapped in a local minimum but also perhaps the conformational change is coupled to protonation or deprotonation or by some physicochemical conditions (pH or temperature). Therefore, before planning a computational experiment you need to search enought informatation about your system to propose the experiment.
If you ask me, I prefer run unbiased atomistic molecular dynamics simulation in the microsecond time scale, than biased methods for the reasons that you mentioned.
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I'm using MST to investigate protein-protein inteactions. Everything seems to be set up properly, no negative outcomes in the binding check. However, I keep on getting inconsistent traces from the same complex sample. No aggregates just different traces every time. I tried different incubation times at room temperature and on ice from 5min to 2h but nothing seems to resolve the issue. Sometimes the complex trace is above the target-only trace and sometimes below. In few cases the two traces are the same. What could be going wrong?
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For most biophysical techniques you need highly pure and stable protein to obtain reliable results. All protein preparations that I use to determine affinities were purified by SEC, then checked with SDS-PAGE and high resolution mass for size, and by DLS for aggregation. If the preparation passes all of these tests, I typically don't have to worry about its behavior in the assay. In your case it is difficult to judge where to start improving the assay, because all of these parameters are unclear from the information you provide. It could be that you purified a protein complex and this is not stable in the buffer you use, that's why it aggregates. Or you concentrated it too high and it doesn't like that. Then the MST trouble shooting won't help because the problem is the protein preparation. I would make sure to have a high quality protein preparation and then follow the MST guidelines for troubleshooting (different capillaries, BSA, Tween-20 addition etc.). If this doesn't work, then use a different technique other than MST because for several systems it just doesn't work.
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Metabolic pathways have key enzymes that are responsible for the catabolism of irreversible reactions and such points are metabolic regulatory points.
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Absolutely. Our lab, for instance, has been working to develop inhibitors of glutaminase enzymes, for instance, which play a major role in supporting oncogenic growth. A number of other groups are pursuing such inhibitors as well, including some big players such as Astra Zeneca and Sanofi. And that's just one protein target. If you check the literature, you'll see that there are groups trying to inhibit various enzymes in the glycolytic pathway, nutrient import receptors, etc. It seems especially prominent in cancer research, but auto-immune diseases rely on hyperactivation of the immune system, which behaves much like cancer, metabolically speaking.
The major challenge, as always, is toxicity. Since all cells need metabolism, you have to try and drug targets that are more important in your disease system than in healthy cells.
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Can anyone suggest me the precise and new anti-cancer target for docking of peptide type compounds. As per literature reports the chemical class of the above peptides are mitotic inhibitors. The BAX and BID along with Caspase 3 were highly expressed with peptides while in cytotoxicity studies. When the above genes are over expressing (Biomarkers) is an indication of apoptosis. Can I choose Caspase 3 as druggable target for these compounds and go for docking ?
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If an article suggests the intracellular protein inhibition for the induction apoptosis in cancer would it be feasible to inhibit the pathway by inhibiting the membrane proteins or receptor tyrosine kinase, as the peptide based drugs are more of surface acting molecules
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May I know the upcoming international conferences/symposiums happening in USA in the field of Lifescience/ Nutraceuticals / Biotechnology/Computer aided drug discovery
Thank you
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7th biomedical multithematic conference hosted by european university cyprus medical school.
it is hosted every year and its 3 days conference. Various participants .
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I've read claims that a cell line with an NLK Knockout is "great for drug discovery." I realize I need to search the literature and read what is out there, but I'm short on time and overworked at the moment. I am hoping someone can steer me in the right direction.
How about it? Could someone throw a fellow scientis
a bone?
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Simple point. in this cell line the gene NLK was knocked out and thereby the expressed protein and its function is lost in these cells.
Now, you have to find out what is the function of NLK in human. Thus, I would propose to perform a PubMed (https://www.ncbi.nlm.nih.gov/pubmed/) search or use other sources for information, such as the various NCBI tools (https://www.ncbi.nlm.nih.gov/).
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I'm planning to propose a project on pipeline of novel drug Discovery
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Can follow the general criteria, source , extraction, purification, detect the structure using physical, chemical & spectroscopic techniques.
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Is the substrate itself hydrophobic, such that it might interact with the detergent?
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Does anyone know what the end-goal of developing artificial intelligence for aiding the drug discovery process is? How would that theoretically work?
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I have gave some pdfs.
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I start this discussion so we can all share our favourites books on cell signaling or signal transduction. I am highly interested in GPCRs.
So I will start first.
"G Protein-Coupled Receptors: Structure, Signaling, and Physiology" by Sandra Siehler, Graeme Milligan is my favourite book so far.
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For a deeper/broader understanding, I suggest you start with:
Cellular Signal Processing: An Introduction to the Molecular Mechanisms of Signal Transduction 2nd Edition
by Friedrich Marks, Ursula Klingmüller, Karin Müller-Decker
I like its approach to cellular signaling and it shows how GPCRs fit into the
signal processing apparatus of the cell.
Then you can dive into:
G Protein-coupled Receptors: Molecular Pharmacology
by Georges Vauquelin, Bengt von Mentzer
None of the books capture the latest developments in GPCR biology as
the field is moving very fast. For this you have reviews by experts.
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There are many research articles exploring alpha glucosidase, salivary and pancreatic alpha amylase inhibition as a therapeutic target for reducing postprandial hyperglycemia (PPHG) in type 2 diabetes. Out of these three, which one is more important/superior and why?
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pancreatic alpha shares higher proportion as conmpared to salivary which makes it better. is this the main reason?
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I would like to request the Researchers to let me know any procedures or references to carryout synthesis of Schiff bases of 4-Aminosalicylic acid when treated with different substituted benzaldehydes, which results in good yields and requires simple work-up (high atom efficient other than Ultrasound technique or Microwave)
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K.A.Shaikh, V.A.Patil, A.M.Zamir ‘‘Solid phase promoted greener synthesis andantibacterial activity of novel Schiff base under catalytically free condition’’ Elixir Org. Chem., 43, 6960-6963(2012
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I want to know if there is an online server for ligand-protein complex docking with another protein. The available renowned protein-protein docking servers like ClusPro, HADDOCK, PyDock etc. either remove or give an error when I try to upload the ligand-protein complex as the receptor pdb file. How can I verify that binding of a ligand to a receptor induces a conformational change or directly blocks the interacting surface in which the native proteins couldn’t bind effectively thereafter?
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Ardavan Abiri If i understand correctly, you have a protein-A with bound ligand and you wish to dock another protein-B to this ligand-protein complex.
Well its true that protein-protein docking softwares do not handle ligand well.
Now i am presuming you have two conformations of protein-A :- (1) its native state and (2) protein-A bound to the ligand which has undergone a conformational change upon binding.
In such cases you can first dock protein-A (native state) with protein-B and predict the interface. Then you can dock the alternative conformation of protein-A with protein-B.
You can then compare the top predicted interfaces between the two types of docking experiments. If the ligand disrupts the binding, then this comparison of docking experiments might provide an indicator.
hope this helps.
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I have synthesised a compound which is inhibiting the enzyme at higher concentration of 150 microgram per ml (IC50=150 microgram) but not cytotoxic to cells even above 1000 microgram per ml can that a potent drug molecule?
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Thank you for your nice work, but the inhibitory effect of specific enzyme selective or no involves invivo or invitro and the conversation of a chemical compound with specific therapeutic action into drug required full data about pharamaco kinetics and dynamics as well as clinical research and toxicology analysis
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SWISSDRUG Filter is efficient tool to screen Fragments for drug Discovery?
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hello some more details of the work involved please
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The aggregation of the 42-residue form of the amyloid-β peptide
(Aβ42) is a pivotal event in Alzheimer’s disease (AD). To solve this question, we want to perform molecular dynamics approach to develop a rational drug discovery strategy against Aβ42 aggregation at molecular level. In fact, the kenetic aggregationof Aβ42 has been stuied recently, understanding the deggreagation design of Aβ42 is also important when small molecules (i.e., drug molecules) get into the activate site.
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There are several problems regarding the study by molecular dynamics (MD) of the effect of ligands on amyloid aggregation:
1. Choice of the amyloid aggregate. There are several structures in the PDB depository. Most of them are NMR structures of AB1-40, the most toxic species. For starters you should choose one of them for your studies.
2. Starting location and pose of your ligand. You could try 'docking' your ligand in some position, guided by software like GOLD, DOCK, etc. Then, you should take some of the results as the starting point for parallel MD simulations
3. The environment. You should try your simulations in water and lipid bi-layers. The latter environment favors the formation of non-helical structures that are found in aggregates.
You are advised to review the literature as some of the issues raised here have been already been dealt with previously.
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I recently started my PhD in microbiology and antibiotics research. For (a part of) my project, my team collaborates with a chemistry lab, that provides new compounds while we have the means to screen for any inhibitory/antibacterial activity (on both purified proteins and model strains).
Today I discussed my idea to start using computational methods with my supervisor and he is sceptical (to say the least) whether those are beneficial at all considering his professional experience.
I have been interested in computer-aided drug design (CADD) for a quite a while now and from looking through the literature and after taking a course on Pharmaceutical Bioinformatics, I got the impression that most drug design projects involve computational methods (Docking, (3D-)QSAR modeling, Pharmacophore modeling, machine learning, etc.) especially at early stages.
However, my experience is limited and my opinion might be biased by my interest.
So two questions arise:
1) What are your experiences concerning contribution of CADD to your drug design projects?
2) Given my little experience in this area, do you think that it would be possible to gain a sufficient level of expertise in order to implement CADD-methods in a way that they could contribute to our project in a meaningful way?
Any answer and/or hint appreciated.
Best regards
Heiner
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Molecular modeling is useful: (1) for interpreting relevant experimental data, (2) for exploring the relationships between structure, dynamics, energy, function, and evolution, (3) for generating new ideas (for further computational and experimental research), (4) creating eye-catching pictures and animations.
Molecular modeling is not useful: (1) for making quantitative predictions. (2) for making money.
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European countries and a few more countries have banned use of animals for drug testing, however drug discovery process can not slow down. It is a possibility that bio printed human tissues with and without pathology can accelerate drug transportation studies. Is this a GAME CHANGER?
In Patient care, Bio printed human tissues can provide bedside research(Translational research) for newer ways of solving healthcare issues. Implanting bio printing liver cells, implanting arteries, cardiac patches on damaged hearts, bio printed tissues aiding regenerative medicine. Sounds exciting - do you see this happening in your work?
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Tarun Virmani - Great response, very erudite as well. I just would like to add that the importance of newer methods and a wider collaboration is seen as accelerating progress in this field