Prioritizing Small Sets of Molecules for Synthesis through<i>in‐silico</i>Tools: A Comparison of Common Ranking Methods

Breznik, Marko; Ge, Yunhui; Bluck, Joseph; Briem, Hans; Hahn, David F.; Christ, Clara D.; Mortier, Jérémie; Mobley, David L.; Meier, Katharina

doi:10.1002/cmdc.202200425

Cited by 33 publications

(37 citation statements)

References 119 publications

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“…Additionally, a blind molecular docking was performed to assess the potential binding of each control compound at the site predicted by the DoGSiteScorer tool (assigning a docking score) [ 28 ]. In this study, blind molecular docking showed docking scores of −9.2 to −7.1 Kcal/mol of the control compounds at the Lm TIM dimer interface ( Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

Virtual Screening of Benzimidazole Derivatives as Potential Triose Phosphate Isomerase Inhibitors with Biological Activity against Leishmania mexicana

et al. 2023

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Leishmania mexicana (L. mexicana) is a causal agent of cutaneous leishmaniasis (CL), a “Neglected disease”, for which the search for new drugs is a priority. Benzimidazole is a scaffold used to develop antiparasitic drugs; therefore, it is interesting molecule against L. mexicana. In this work, a ligand-based virtual screening (LBVS) of the ZINC15 database was performed. Subsequently, molecular docking was used to predict the compounds with potential binding at the dimer interface of triosephosphate isomerase (TIM) of L. mexicana (LmTIM). Compounds were selected on binding patterns, cost, and commercial availability for in vitro assays against L. mexicana blood promastigotes. The compounds were analyzed by molecular dynamics simulation on LmTIM and its homologous human TIM. Finally, the physicochemical and pharmacokinetic properties were determined in silico. A total of 175 molecules with docking scores between −10.8 and −9.0 Kcal/mol were obtained. Compound E2 showed the best leishmanicidal activity (IC50 = 4.04 µM) with a value similar to the reference drug pentamidine (IC50 = 2.23 µM). Molecular dynamics analysis predicted low affinity for human TIM. Furthermore, the pharmacokinetic and toxicological properties of the compounds were suitable for developing new leishmanicidal agents.

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Section: Resultsmentioning

confidence: 99%

Virtual Screening of Benzimidazole Derivatives as Potential Triose Phosphate Isomerase Inhibitors with Biological Activity against Leishmania mexicana

et al. 2023

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“…Therefore, more validation methods need to be used jointly for a better prediction. Molecular dynamics-based methods, although computationally expensive, are reported to perform better in ranking molecules compared with docking methods including ChemPLP, AutoDock Vina and Glide [ 23 ]. For example, top ranking molecules selected by a PLP fitness score could be further screened by molecular dynamics-based methods before inhibitor purchasing for experimental verification.…”

Section: Discussionmentioning

confidence: 99%

Search of Novel Small Molecule Inhibitors for the Main Protease of SARS-CoV-2

Zhang

Lin

2023

Viruses

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The current outbreak of coronavirus disease 2019 (COVID-19) has prompted the necessity of efficient treatment strategies. The COVID-19 pandemic was caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Main protease (Mpro), also called 3-chymotrypsin-like protease (3CL protease), plays an essential role in cleaving virus polyproteins for the functional replication complex. Therefore, Mpro is a promising drug target for COVID-19 therapy. Through molecular modelling, docking and a protease activity assay, we found four novel inhibitors targeting Mpro with the half maximal inhibitory concentration (IC50) and their binding affinities shown by the dissociation constants (KDs). Our new inhibitors CB-21, CB-25, CP-1 and LC24-20 have IC50s at 14.88 µM (95% Confidence Interval (95% CI): 10.35 µM to 20.48 µM), 22.74 µM (95% CI: 13.01 µM to 38.16 µM), 18.54µM (95% CI: 6.54 µM to 36.30 µM) and 32.87µM (95% CI: 18.37 µM to 54.80 µM)), respectively. The evaluation of interactions suggested that each inhibitor has a hydrogen bond or hydrophobic interactions with important residues, including the most essential catalytic residues: His41 and Cys145. All the four inhibitors have a much higher 50% lethal dose (LD50) compared with the well-known Mpro inhibitor GC376, demonstrating its low toxicity. These four inhibitors can be potential drug candidates for further in vitro and in vivo studies against COVID-19.

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“…This reinforces conclusions in an earlier paper by Hou et al [ 69 ]. Other reports suggest that MM/PBSA binding energies were better for ranking than docking scoring functions [ 70 ], while others have shown no significant difference [ 71 ], with both being less effective than MD alchemical methods. Our prior studies on repurposing drugs active against SARS-CoV-2 enzyme targets also established a strong correlation between MM/PBSA energies and those calculated from a thermodynamic cycle [ 9 , 11 ].…”

Section: Methodsmentioning

confidence: 99%

Identifying SARS-CoV-2 Drugs Binding to the Spike Fatty Acid Binding Pocket Using In Silico Docking and Molecular Dynamics

Piplani

Singh

Petrovsky

et al. 2023

IJMS

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Drugs against novel targets are needed to treat COVID-19 patients, especially as SARS-CoV-2 is capable of rapid mutation. Structure-based de novo drug design and repurposing of drugs and natural products is a rational approach to discovering potentially effective therapies. These in silico simulations can quickly identify existing drugs with known safety profiles that can be repurposed for COVID-19 treatment. Here, we employ the newly identified spike protein free fatty acid binding pocket structure to identify repurposing candidates as potential SARS-CoV-2 therapies. Using a validated docking and molecular dynamics protocol effective at identifying repurposing candidates inhibiting other SARS-CoV-2 molecular targets, this study provides novel insights into the SARS-CoV-2 spike protein and its potential regulation by endogenous hormones and drugs. Some of the predicted repurposing candidates have already been demonstrated experimentally to inhibit SARS-CoV-2 activity, but most of the candidate drugs have yet to be tested for activity against the virus. We also elucidated a rationale for the effects of steroid and sex hormones and some vitamins on SARS-CoV-2 infection and COVID-19 recovery.

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Prioritizing Small Sets of Molecules for Synthesis throughin‐silicoTools: A Comparison of Common Ranking Methods

Cited by 33 publications

References 119 publications

Virtual Screening of Benzimidazole Derivatives as Potential Triose Phosphate Isomerase Inhibitors with Biological Activity against Leishmania mexicana

Virtual Screening of Benzimidazole Derivatives as Potential Triose Phosphate Isomerase Inhibitors with Biological Activity against Leishmania mexicana

Search of Novel Small Molecule Inhibitors for the Main Protease of SARS-CoV-2

Identifying SARS-CoV-2 Drugs Binding to the Spike Fatty Acid Binding Pocket Using In Silico Docking and Molecular Dynamics

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