Document Type
Article
Publication Date
11-2021
Publication Title
Methods
Volume
195
Pages
57-71
Publisher Name
Elsevier
Abstract
SARS-CoV-2, the virus that causes COVID-19 consists of several enzymes with essential functions within its proteome. Here, we focused on repurposing approved and investigational drugs/compounds. We targeted seven proteins with enzymatic activities known to be essential at different stages of the viral cycle including PLpro, 3CLpro, RdRP, Helicase, ExoN, NendoU, and 2′-O-MT. For virtual screening, 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 and investigational molecules (n = 5903). The screening was performed against viral targets using three sequential docking modes (i.e., HTVS, SP, and XP). Virtual screening identified ∼290 potential inhibitors 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. The resulting top eight hits were tested for their SARS-CoV-2 anti-viral activity in-vitro. Among these, a known inhibitor of protein kinase C isoforms, Bisindolylmaleimide IX (BIM IX), was found to be a potent inhibitor of SARS-CoV-2. Further, target validation through enzymatic assays confirmed 3CLpro to be the target. This is the first study that has showcased BIM IX as a COVID-19 inhibitor thereby validating our pipeline.
Identifier
1046-2023
Recommended Citation
Gupta, Yash; Maciorowski, Dawid; Zak, Samantha E.; Jones, Krysten A.; Kathayat, Rahul S.; Azizi, Saara-Anne; Mathur, Raman; Pearce, Catherine M.; Ilc, David J.; Husein, Hamza; Herbert, Andrew S.; Bharti, Ajay; Rathi, Brijesh; Durvasula, Ravi; Becker, Daniel P.; Dickinson, Bryan C.; Dye, John M.; and Kempaiah, Prakasha. Bisindolylmaleimide IX: a Novel Anti-SARS-CoV2 Agent Targeting Viral Main Protease 3CLpro Demonstrated by Virtual Screening Pipeline and In-Vitro Validation Assays. Methods, 195, : 57-71, 2021. Retrieved from Loyola eCommons, Chemistry: Faculty Publications and Other Works, http://dx.doi.org/10.1016/j.ymeth.2021.01.003
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Copyright Statement
© The Authors, 2021.
Included in
Biochemistry Commons, Chemistry Commons, Immunology and Infectious Disease Commons, Medicinal and Pharmaceutical Chemistry Commons
Comments
Author Posting © The Authors, 2021. This article was published Gold Open Access.