Computational Drug Simulation: A Step to the Possible Cure of COVID-19

et al. 2020

Preprint

The emergence of SARS/MERS drug-resistant SARS-CoV2 comes with higher rates of transmission and mortality. Like all coronaviruses, SARS-CoV-2 is a relatively large virus consisting of several enzymes with essential functions within its proteome. Here, we focused on repurposing approved and investigational drugs by identifying potential drugs that are predicted to effectively inhibit critical enzymes. We targeted seven proteins with enzymatic activities known to be essential at different stages of the viral multiplication cycle including PLpro, 3CLpro, RdRP, Helicase, ExoN, NendoU, and 2’-O-MT. For virtual screening, the energy minimization of a crystal structure of the modeled protein was carried out using the Protein Preparation Wizard(Schrodinger LLC 2020-1). Following active site selection based on data mining and COACH predictions, we performed a high-throughput virtual screen of drugs (n=5903) that are approved by worldwide regulatory bodies. The screening was performed against viral targets using three sequential docking modes (i.e. HTVS, SP, and XP). Our in-silico virtual screening identified ~290 potential drugs based on the criteria of energy, docking parameters, ligand, and binding site strain and score. Drugs specific to each target protein were further analyzed for binding free energy perturbation by molecular mechanics (prime MM-GBSA) and pruning the hits to the top 32 candidates. The top lead from each target pool was further subjected to molecular dynamics simulation using the Desmond module. Herein we report the evaluation of in-vitro efficacy of selected hit drug molecules on SARS-CoV-2 inhibition. Among eight molecules included in our evaluation, we found inhibitor of protein kinase C isoforms, Bisindolylmaleimide IX (BIM IX), as the potent inhibitor of SARS-CoV-2 in-vitro. Further, in-silico predicted target validation through enzymatic assays confirmed 3CLpro to be the target. Therefore, our data support advancing BIM IX for clinical evaluation as a potential treatment for COVID-19. This is the first study that has showcased the possibility of using bisindolylmaleimide IX to treat COVID-19 through this pipeline.

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Section: Resultsmentioning

confidence: 99%

Bisindolylmaleimide IX: A novel anti-SARS-CoV2 agent targeting viral main protease 3CLpro demonstrated by virtual screening and in vitro assays

et al. 2020

Preprint

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“…It is shown to have anticancer and antiallergenic activities 69 . Daidzein and Haloperidol have been identi ed in multiple virtual screenings 70,71 . MD Simulation of the Daidzin-NendoU complex for 20ns revealed a stable and energetically favorable interaction and validated the pipeline for the NendoU virtual screening (Supplementary g.6).…”

Section: Resultsmentioning

confidence: 99%

Bisindolylmaleimide IX: A novel anti-SARS-CoV2 agent targeting viral main protease 3CLpro demonstrated by virtual screening and in vitro assays

et al. 2020

Preprint

The emergence of SARS/MERS drug-resistant COVID-19 with high transmission and mortality has recently been declared a pandemic. Like all coronaviruses, SARS-CoV-2 is a relatively large virus consisting of several enzymes with essential functions within its proteome. Here, we focused on repurposing approved and investigational drugs by identifying potential drugs that are predicted to effectively inhibit critical enzymes. We targeted seven proteins with enzymatic activities known to be essential at different stages of the virus life cycle; PLpro, 3CLpro, RdRP, Helicase, ExoN, NendoU, and 2’-O-MT. For virtual screening, the energy minimization of a crystal structure of the modeled protein was carried out using the Protein Preparation Wizard1. Following active site selection based on data mining and COACH predictions, we performed a high-throughput virtual screen of drugs (n=5903) that are approved by worldwide regulatory bodies. The screening was performed against viral targets using three sequential docking modes (i.e. HTVS, SP, and XP). Our in-silico virtual screening identified ~290 potential drugs based on the criteria of energy, docking parameters, ligand, and binding site strain and score. Drugs specific to each target protein were further analyzed for binding free energy perturbation by molecular mechanics (prime MM-GBSA) and pruning the hits to the top 32 candidates. Top lead from each target pool was further subjected to molecular dynamics simulation using the Desmond module. Herein we report the evaluation of in-vitro efficacy of selected hit drug molecules on SARS-CoV-2 virus inhibition. Among eight molecules included in our evaluation, we found the micromolar inhibitor of protein kinase C isoforms, Bisindolylmaleimide IX (BIM IX), as the most potent inhibitor of SARS-CoV-2 in-vitro. Further, in-silico predicted target validation through enzymatic assays confirmed its interaction with 3CLpro to be the target. Therefore, our data support advancing BIM IX for clinical evaluation as a potential treatment for COVID-19. This is the first study that has showcased the possibility of using bisindolylmaleimide IX to treat COVID-19 through this pipeline.

show abstract

Bisindolylmaleimide IX: A novel anti-SARS-CoV2 agent targeting viral main protease 3CLpro demonstrated by virtual screening pipeline and in-vitro validation assays

et al. 2021

Methods