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(a) The crystal structure showing the binding of Dorzolamide (orange) to carbonic anhydrase II (purple) (4M2U) (b) the structure of Dorzolamide. Dorzolamide is an FDA approved drug that targets carbonic anhydrase II to treat patience with glaucoma.
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The process for drug discovery and development is challenging, time consuming and expensive. Computer-aided drug discovery (CADD) tools can act as a virtual shortcut, assisting in the expedition of this long process and potentially reducing the cost of research and development. Today CADD has become an effective and indispensable tool in therapeuti...
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... another study, structure-based computational methods have been used to predict binding sites, which are important for in- hibitor binding, in AmpC beta lactamase which have been ex- perimentally verified [17]. FDA approved Dorzolamide is a carbonic anhydrase II inhibitor which is used in the treatment of glaucoma and was developed using structure-based tools (Figure 3) [7,8]. ...
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... Recently, fourier-transform infrared (FTIR) spectroscopy and gas chromatography-mass spectrometry (GC-MS) have become standard methods for detecting functional groups and identifying various therapeutic compounds present in medicinal plants (Fan et al., 2018;Satapute et al., 2019). Further, in recent times, computer-aided tools have become crucial in drug discovery, enabling the screening of phytochemicals from medicinal plants (Leelananda & Lindert, 2016). These computational prediction models, also known as predictive tools, play a vital role in guiding pharmaceutical and technological research by forecasting pharmacological, pharmacokinetic, and toxicological properties (Loza-Mejía et al., 2018). ...
Potentilla fulgens Wall ex Sims., a local medicinal plant used by the Khasi tribe of Meghalaya, India, has been reported to be rich in tannins, polyphenols, triterpenoids, and flavonoids. Although several studies have been conducted on its antidiabetic and anti-oxidant properties, most reports were done with crude polar extracts. In this study, we report the inhibitory effect of the non-polar chloroform extract of P. fulgens (NPFE) on α- amylase and α- glucosidase. The extract exhibited a potent antioxidant effect comparable to the reference standard as reflected by the IC50 values in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. Further, the antihyperglycemic action of NPFE was observed in alloxan-induced diabetic mice from the Intraperitoneal Glucose Tolerance Test (IPGTT). Spectral and chromatographic analysis using FTIR and GC-MS/MS showed the presence of important functional groups and bioactive compounds. In silico molecular docking of the identified bioactive compounds carried out against α-amylase and α-glucosidase provided more insights into its antihyperglycemic properties.
... Drug discovery [1] is an arduous journey with many unknowns all along the path, with several traps that lead to failure. To perform large number of trials in an iterative manner, computer simulations [2,3] come in handy to perform tens of thousands of calculations to provide crucial insights and rule out dead ends. Structure-based drug discovery (SBDD) is one such approach that aids in designing and optimizing chemical entities by leveraging the tertiary structural information of biological targets. ...
Molecular docking is a useful method for predicting the binding affinity and conformation of small chemical entities to support lead optimisation. It is also used to virtually screen a large chemical database to find new chemical entities. There are several docking programs available with different algorithms and varying preparation steps. We identify ten quick tips that apply to molecular docking irrespective of the program one might choose. Our objective is to provide the beginners with important things to keep in mind while using molecular docking for their research. We aim to ensure that experts and beginners can perform molecular docking to yield biologically relevant and reproducible results.
... Computational methods have become indispensable tools in modern drug discovery, offering insights into protein-ligand interactions and enabling the identification of promising candidates with drug-like properties 46,47 . Techniques such as molecular docking, molecular dynamics (MD) simulations, and free energy calculations provide a detailed mechanistic understanding at the atomic level 48,49 . ...
The regulation of the mammalian target of rapamycin (mTOR) protein by cancer cells can lead to uncontrol of cancer cell growth and cancer therapy resistance. The drug discovery of the anticancer agent 5-(3-hydroxy-4-methoxyphenethyl)-2-methoxy-3-methylphenol (SM-3), a derivative of resveratrol by substituting a methyl group at the hydroxy group of ring A and adding a methoxy group at the para position of ring B, shows promising potential for targeting autophagy to induce cell death and suppress cancer stem cells (CSCs) through the inhibition of the mTOR protein. In human lung cancer cells, SM-3 showed greater efficacy, with lower IC50 values of 72.74 ± 0.13, 67.66 ± 0.10, and 43.24 ± 0.11 µM in A549, H292, and H460 cells, respectively, compared to the parent compound, Resveratrol (Res). Moreover, the selectivity index (SI) values for BEAS2B cells compared to tumor cells treated with SM-3 were 10.99, 11.81, and 18.49 for A549, H292, and H460 cell lines, respectively. Therefore, SM-3 treatment led to reduced proliferation rates and colony formation in lung cancer cells. In our study, spheroids treated with SM-3 showed a higher proportion of dead spheroids compared to those treated with Res. Additionally, SM-3 treatment resulted in decreased expression of stem cell markers (CD133, CD44, and ALDH1A1) and transcription factors (OCT4, NANOG, and SOX2) in spheroids and organoids from human lung cancer cells by inhibiting the mTOR/pAkt pathway. SM-3 was also found to induce autophagic cell death, as indicated by Monodansylcadaverine staining, acidic vesicle formation, and the conversion of LC3BI to LC3BII. Using MM/GBSA calculations, SM-3 exhibited a stronger binding affinity (-25.09 kcal/mol) compared to Res (-18.85 kcal/mol). SM-3 also displayed greater stability during the entire simulation, maintaining lower RMSD values of 2–3 Å even after 80 ns. In summary, the introduction of methyl and methoxy functional groups on Res to create SM-3 effectively suppressed cancer spheroids and organoids formation in lung cancer cells by targeting the upstream mTOR/pAkt pathway.
... The small molecule MAO-B inhibitor compound, indole-3-carbinol was discovered through QSAR approach. However, its low potency hampered the compound's further development but the optimized analog SR13668 of indole-3-carbinol identified through ligand-based pharmacophore modeling emerged as a potent anticancer agent effective against different types of cancer (Chao et al., 2007;Leelananda & Lindert, 2016). Jin et al. (2020) employed a fragment-based design approach for the discovery of potent and selective monoamine oxidase B inhibitors. ...
The discovery of a safe and efficacious drug is a complex, time-consuming, and expensive process. Computational methodologies driven by cheminformatics tools play a central role in the high-throughput lead discovery and optimization process especially when the structure of the biological target is known. Monoamine oxidases are the membrane-bound FAD-containing enzymes and the isoform monoamine oxidase-B (MAO-B) is an attractive target for treating diseases like Alzheimer’s disease, Parkinson’s disease, glioma, etc. In the current study, we have used a pharmacophore-based virtual screening technique for the identification of new small molecule MAO-B inhibitors. Safinamide was used for building a pharmacophore model and the developed model was used to probe the ZINC database for potential hits. The obtained hits were filtered against drug-likeness and PAINS. Out of the hit’s library, two compounds ZINC02181408, ZINC08853942 (most active), and ZINC53327382 (least active) were further subjected to molecular docking and dynamics simulation studies to assess their virtual binding affinities and stability of the resultant protein–ligand complex. The docking studies revealed that active ligands were well accommodated within the active site of MAO-B and interacted with both substrate and entrance cavity residues. MD simulation studies unveiled additional hydrogen bond interactions with the substrate cavity residues, Tyr398 and Tyr435 that are crucial for the catalytic role of MAO-B. Moreover, the predicted ADMET parameters suggest that the compounds ZINC08853942 and ZINC02181408 are suitable for CNS penetration. Thus, the attempted computational campaign yielded two potential MAO-B inhibitors that merit further experimental investigation.
... The small molecule MAO-B inhibitor compound, indole-3-carbinol was discovered through QSAR approach. However, its low potency hampered the compound's further development but the optimized analog SR13668 of indole-3-carbinol identified through ligand-based pharmacophore modeling emerged as a potent anticancer agent effective against different types of cancer (Chao et al., 2007;Leelananda & Lindert, 2016). Jin et al. (2020) employed a fragment-based design approach for the discovery of potent and selective monoamine oxidase B inhibitors. ...
A series of novel benzimidazole-derived carbohydrazones was designed, synthesized and evaluated for their dual inhibition potential against monoamine oxidases (MAOs) and acetylcholinesterase (AChE) using multitarget-directed ligand approach (MTDL). The investigated compounds have exhibited moderate to excellent in vitro MAOs/AChE inhibitory activity at micromolar to nanomolar concentrations. Compound 12, 2-(1H-Benzo[d]imidazol-1-yl)-N'-[1-(4-hydroxyphenyl) ethylidene]acetohydrazide has emerged as a lead dual MAO-AChE inhibitor by exhibiting superior multi-target activity profile against MAO-A (IC50 = 0.067 ± 0.018 µM), MAO-B (IC50 = 0.029 ± 0.005 µM) and AChE (IC50 = 1.37 ± 0.026 µM). SAR studies suggest that the site A (hydrophobic ring) and site C (semicarbazone linker) modifications attempted on the semicarbazone-based MTDL resulted in a significant enhancement in the MAO-A/B inhibitory potential and a drastic decrease in the AChE inhibitory activity. Further, molecular docking and dynamics simulation experiments disclosed the possible molecular interactions of inhibitors inside the active site of respective enzymes. Also, computational prediction of drug-likeness and ADME parameters of test compounds revealed their drug-like characteristics.
... Thus, the theoretical or predicted anticancer results for most of the compounds were supported by the experimental results. Machine learning prediction scores, including those from various algorithms, remained relatively consistent across most compounds, highlighting that comprehensive analysis incorporating multiple descriptors, rather than reliance on a single functional group, is crucial for accurately predicting biological activity (Velmurugan et al., 2020;Leelananda and Lindert, 2016). The general SAR of the synthesized compounds was highlighted in Fig. 14. ...
... A threshold value of -6 kcal/mol is regularly used to identify potential hits. [38,39] In this have a look at, molecules with a ΔG_bind of ≤ -6 kcal/mol have been taken into consideration as hits or promising candidates. The docking analysis (Table 1) indicated that 40 out of 164 phytochemicals didn't gain binding energies of ≤ -6 kcal/ mol with any target. ...
Snake envenomation leads to about 125,000 deaths yearly worldwide, with India accounting for almost 50,000 of these fatalities. Even as antivenoms remain the primary treatment, they have limitations, prompting the exploration of phytochemicals from Calotropis gigantea as potential multi-target therapies against cobra venom toxins. About 14 venom proteins, namely phospholipase A2 (PLA2), cobrotoxin, L-amino acid oxidase, acetylcholinesterase, cobramin A, cobramin B, cytotoxin 3, long neurotoxins 1 to 5, serine protease and proteolase were the selected targets. The 3D structures of those venom proteins were downloaded from the protein data bank and SWISS-MODEL. A complete of 164 phytochemicals from C. gigantea were docked using AutoDock Vina and PyRx 8.0 to assess their binding capability. Compounds with binding energies ≤ -6 kcal/mol have been selected as hits based on their multi-target activity. Subsequently, absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties and molecular interactions of these molecules were analyzed, with choice standards specializing in binding affinity and pharmacokinetics. Molecular dynamics simulations over 100 ns, completed the usage of GROMACS 2018.1, identified β-amyrin and lupeol as effective inhibitors of PLA2, acetylcholinesterase, and cobrotoxin. Lupeol exhibited greater constancy throughout simulations, at the same time as β-amyrin more suitable enzyme structure stabilization. Both compounds demonstrated good pharmacokinetics, though issues such as low solubility and potential cardiac dangers warrant further research.
... The thiopyranoindole heterocycles are also noteworthy due to their medicinal properties [12] . Among the important heterocycles, the isoxazolidines have a particular importance and are considered a useful class abundant in compounds [13] . Some isoxazolidine derivatives exhibit antifungal [14] , anti-inflammatory [15] , antimycobacterial [16] , and cytotoxic activities [17] , and they also act as DNA intercalators [18] . ...
In this paper, an MEDT computational study was conducted through the B3LYP/6-31G(d,p) DFT method, to analyse the mechanism nature and the selectivities of the intramolecular [3+2] cycloaddition (I32CA) of the (E)-N-((2-((methylbut-2-en-1-yl)thio)-1H-indol-3-yl)methylene)methanamine oxide. The investigation covered the three potential pathways, including the fused endo and exo steric approaches and the bridged channels associated with the I32CA reaction. Analysis of relative energy indicated that the isoxazolidine formed from the fused-endo pathway is favored kinetically, which are consistent with the published experimental findings. Based on bond order values and geometry of the transition states, the obtained results suggest that this I32CA occurs via one-step slightly synchronous mechanism in the case of the fused modes, whereas in the bridged one via a one-step slightly asynchronous mechanism. Relative thermodynamic functions show that the studied I32CA has exothermic and exergonic behaviours. ELF analysis of the fused-endo pathway reveals that the mechanism of this I32CA reaction is non-concerted slightly synchronous two stages one-step. NCI and QTAIM analyses show that the existence of several NCIs at the favourable fused-endo structure is the main reason for the fused-endo selectivity.
... Computer aided drug design (CADD) allows for the rapid mass screening of thousands of potential ligands against several protein targets (Yu et al. 2017). CADD can also predict whether a compound has the features of an "ideal" drug, such as, bioavailability, distribution to target tissues, metabolically stable, long half-life, and nontoxic (Leelananda and Lindert 2016). Structure-based drug design (SBDD) is a powerful approach to drug design. ...
Inhibition of pancreatic alpha-amylase and alpha-glucosidase is a common strategy to manage type 2 diabetes. This study focuses on the ability of compounds present in commercially available herbs and spices to inhibit pancreatic alpha-amylase and alpha-glucosidase. In silico molecular docking was performed to evaluate the binding affinity of the compounds present in herbs and spices. Molecular dynamics was performed with acarbose and rutin which had the best docking scores for pancreatic alpha-amylase and alpha-glucosidase. Six compounds (rutin, caffeic acid, p-coumaric acid, vanillin, ethyl gallate, and oxalic acid) with a range of docking scores were subjected to in vitro enzyme kinetic studies using pancreatic alpha-amylase and alpha-glucosidase biochemical assays. Acarbose, a prescribed alpha-amylase and alpha-glucosidase inhibitor, was used as a positive control. Ligands that interacted strongly with the amino acids at a particular site, were conformationally stable and had good docking scores. There was a correlation between the in silico and in vitro binding affinity. Caffeic acid, vanillin, ethyl gallate, and p-coumaric acid had inhibition constant (Ki) values that were not significantly different (p > 0.05) from the Ki of acarbose for pancreatic alpha-amylase. Rutin, caffeic acid, vanillin, and p-coumaric acid had Ki values that were not significantly different (p ˃ 0.05) from the Ki of acarbose for alpha-glucosidase. The cell viability of these compounds was assessed with the sulforhodamine B (SRB) assay in Caco2 cells. Caffeic acid, p-coumaric acid, rutin, and vanillin had Caco2 IC50 values that were not significantly different (p ˃ 0.05) from that of acarbose. The evaluated compounds present in herbs and spices can potentially reduce hyperglycemia associated with type 2 diabetes. Herbs and spices with high levels of these compounds were identified and these were common verbena, sweet basil, tarragon, pepper, parsley, sorrel, and vanilla. These herbs and spices may reduce the required dose of prescription drugs, such as acarbose, thereby reducing costs and drug-associated side effects.
... This study utilized structural-based pharmacophore modeling, molecular docking, molecular dynamics simulations, and ADMET predictions to discover potential inhibitors of ASK1 [57][58][59][60][61][62][63][64][65]. ...
Apoptosis Signal Regulating Kinases 1 (ASK 1) is an upstream kinase in the MAPK superfamily. It carries out phosphorylation of other members within the family, leading to the activation of the P38 MAPK pathway and C-JUN-N-terminal kinases. The onset of this activation cascade occurs through the phosphorylation of extracellular protein kinases (EPKs) which triggers different stimuli like pro-inflammatory cytokines, environmental factors, and internal stressors. These proteins are also known as stress-activated protein kinases (SAPKs) that are linked to various pathological conditions, yet effective inhibitors for this protein have not been witnessed. This study used structural-based pharmacophore modeling, molecular docking, molecular dynamics simulations, and ADMET predictions to identify the compounds that can potentially inhibit ASK1. Based on the SN3 database, 4160 natural compounds were evaluated for their pharmacophoric characteristics. Subsequently, the distinguished compounds in this step underwent MMGBSA calculations and docking. Compounds SN0030543, SN035314, and SN0330056 exhibited XP higher docking score values (− 14.240 kcal/mol, 12.00 kcal/mol, and − 11.054 kcal/mol, respectively) than that of the bound ligand (− 10.785 kcal/mol). After undergoing 100 nano-second molecular dynamics studies, these compounds displayed durable interactions with the ASK1 binding site. These substances should be given priority for validation as ASK1 inhibitors in upcoming experiments.
