Computational screening and identifying binding interaction of anti-viral and anti-malarial drugs: Toward the potential cure for SARS-CoV-2

Lee, Vannajan Sanghiran; Chong, Wei Lim; Sukumaran, Sri Devi; Nimmanpipug, Pivarat; Letchumanan, Vengadesh; Goh, Bey Hing; Lee, Learn‐Han; Zain, Sharifuddin M.; Rahman, Noorsaadah Abd.

doi:10.36877/pddbs.a0000065

Cited by 28 publications

(22 citation statements)

References 8 publications

(8 reference statements)

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“…This compound is FDA approved for use in adult patients infected with HIV-1. Nevirapine has also been revealed in various in-silico drug screening with the main protease 115,116 . Pentostatin is a purine analog that is widely used as a treatment for hairy cell leukemia 117 .…”

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

Gupta

Maciorowski

Zak

et al. 2020

Preprint

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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

Gupta

Maciorowski

Zak

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Nevirapine has also been revealed in various in-silico drug screening with the main protease 117,118 . Pentostatin is a purine analog that is widely used as a treatment for hairy cell leukemia 119 .…”

Section: Resultsmentioning

confidence: 99%

“…Similar to pentostatin, cladribine is also a therapy for hairy cell leukemia. And also like nevirapine, cladribine has been predicted to block main protease 3CLpro in many reports 118,120 . Bisindolylmaleimide IX a PKC inhibitor was strongly bound to 3CLpro for a 100 ns simulation ( Fig.3&5(A)) and the stable complex exhibited a tight binding with the whole molecule involved in interactions with 3CLpro active site side-chain amino acid residues ( Fig.3…”

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

Gupta

Maciorowski

Zak

et al. 2020

Preprint

View full text Add to dashboard Cite

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.

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“…However, some of predictions have been showed by recent literature to be bene cial for COVID-19. For instance, recent computational studies offer Cidofovir, Deferoxamine, Cytarabine and Clarithromycin as potent drugs for COVID-19 treatment [50][51][52][53]. ACE2-associated network analysis suggest a crucial role of Fluticasone propionate for COVID-19 treatment [54].…”

Section: Discussionmentioning

confidence: 99%

Transcriptional analysis of lung epithelial cells using WGCNA revealed the role of IRF9 and IFI6 genes in SARS-CoV-2 pathogenicity

Karami

Derakhshani

Fereidouni

et al. 2020

Preprint

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The coronavirus disease 2019 (COVID-19) outbreak is an ongoing global health emergence, but the pathogenesis remains unclear. Here, we applied weighted gene co-expression network analysis to comprehensively characterize transcriptional changes in bronchial epithelium cells (NHBE and A549 cells) during SARS-CoV-2 infection. Our analysis identified a network highly correlated to COVID-19 pathogenicity based on MX1, IFIT1, ISG15, IFI6, DDX60, IRF9, PARP9, PGLYRP4, IL36G, SAA2 and IL-8 hub genes. The results also indicated a unique transcriptional signatures of infected cells including IFI6 and IRF9 as novel gene candidates and suggested their prospective mechanism in COVID-19 pathogenesis. The result of hub genes enrichment showed that the most correlation topic in biological process and KEGG were type I interferon signaling pathway, IL-17 signaling pathway, cytokine mediated signaling pathway, and defense response to virus categories which all play significant roles in restricting viral infection. Also according to the drug-target network, we recognized 54 FDA-approved drug candidates for other indications could potentially use for the treatment of COVID-19 patients through regulation of six hub genes of the co-expression network. Our findings also showed that the 19 experimentally validated miRNAs regulated the co-expression network through 5 hub genes (SLC19A3, FAM13A, PLA2G16, and HRASLS5). In conclusion, these hub genes had potential roles in the translational medicine and might become promising therapeutic targets further in vitro and in vivo experimental studies are needed to evaluate the role of above mentioned genes in COVID-19.

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Computational screening and identifying binding interaction of anti-viral and anti-malarial drugs: Toward the potential cure for SARS-CoV-2

Cited by 28 publications

References 8 publications

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

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

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

Transcriptional analysis of lung epithelial cells using WGCNA revealed the role of IRF9 and IFI6 genes in SARS-CoV-2 pathogenicity

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