Science topic
Drug Discovery - Science topic
The process of finding chemicals for potential therapeutic use.
Questions related to Drug Discovery
I am here for specific answers or a list of investigation tools to determine the newly developed drugs/inhibitors/medicines.
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!
Are there certain precautions while preparing zinc fingers - containing proteins for MOLECULAR DYNAMICS SIMULATION?
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?
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!
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
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
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?
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.
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 :)
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
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?
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
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
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.
We are doing research in cancer drug discovery so can anyone suggest me a new Bio-info tool for drug screening.
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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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.
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
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.
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.
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
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.
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)
i have a crystal structure at the allosteric site but need to prove the worth of that allosteric site what experiments can be performed?
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?
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?
To get ligands after submitting target protein (.pdb file)
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.
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?
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.
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."
see also this paper: https://academic.oup.com/jac/article/74/7/1769/5359493
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."
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.
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 ?
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.
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
Could we think about drug molecules without small molecules? I mean less introduce foreign particles in our body.
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
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?
How are Artificial intelligence and Machine Learning boosting COVID-19 drug discovery process?
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?
I just want to know the cells should be viewed under which filter.
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?
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.
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?
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.
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?
I am looking for databases that contain microRNA-drug interactions. Any suggestions or recommendations?
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?
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?
Metabolic pathways have key enzymes that are responsible for the catabolism of irreversible reactions and such points are metabolic regulatory points.
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 ?
May I know the upcoming international conferences/symposiums happening in USA in the field of Lifescience/ Nutraceuticals / Biotechnology/Computer aided drug discovery
Thank you
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?
I'm planning to propose a project on pipeline of novel drug Discovery
Does anyone know what the end-goal of developing artificial intelligence for aiding the drug discovery process is? How would that theoretically work?
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.
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?
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)
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?
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?
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
SWISSDRUG Filter is efficient tool to screen Fragments for drug Discovery?
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.
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
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?
