Quantitative structure-activity relationships, molecular docking and molecular dynamics simulations reveal drug repurposing candidates as potent SARS-CoV-2 main protease inhibitors. Issue 21 (5th December 2022)

• Record Type: Journal Article
• Authors: de Souza, Anacleto Silva; de Souza, Robson Francisco; Guzzo, Cristiane Rodrigues
• Is Part Of: Journal of biomolecular structure & dynamics. Volume 40:Issue 21(2022)
• Page Start: 11339
• Page End: 11356
• Publication Date: 2022-12-05
• Subjects: QSAR models -- high-throughput virtual screening -- pKi prediction -- SARS-CoV-2 -- molecular dynamics simulations; Biomolecules -- Periodicals; Molecular structure -- Periodicals; Molecular Biology -- Periodicals; Biomechanics -- Periodicals; 572
• DOI: 10.1080/07391102.2021.1958700
• Languages: English
• ISSNs: 0739-1102

Abstract

Abstract: The current outbreak of COVID-19 is leading an unprecedented scientific effort focusing on targeting SARS-CoV-2 proteins critical for its viral replication. Herein, we performed high-throughput virtual screening of more than eleven thousand FDA-approved drugs using backpropagation-based artificial neural networks ( q 2 LOO = 0.60, r 2 = 0.80 and r 2 pred = 0.91), partial-least-square (PLS) regression ( q 2 LOO = 0.83, r 2 = 0.62 and r 2 pred = 0.70) and sequential minimal optimization (SMO) regression ( q 2 LOO = 0.70, r 2 = 0.80 and r 2 pred = 0.89). We simulated the stability of Acarbose-derived hexasaccharide, Naratriptan, Peramivir, Dihydrostreptomycin, Enviomycin, Rolitetracycline, Viomycin, Angiotensin II, Angiotensin 1-7, Angiotensinamide, Fenoterol, Zanamivir, Laninamivir and Laninamivir octanoate with 3CLpro by 100 ns and calculated binding free energy using molecular mechanics combined with Poisson-Boltzmann surface area (MM-PBSA). Our QSAR models and molecular dynamics data suggest that seven repurposed-drug candidates such as Acarbose-derived Hexasaccharide, Angiotensinamide, Dihydrostreptomycin, Enviomycin, Fenoterol, Naratriptan and Viomycin are potential SARS-CoV-2 main protease inhibitors. In addition, our QSAR models and molecular dynamics simulations revealed that His41, Asn142, Cys145, Glu166 and Gln189 are potential pharmacophoric centers for 3CLpro inhibitors. Glu166 is a potential pharmacophore for drug design and inhibitors that interact with this residue may be critical to avoid dimerization of 3CLpro . Our results will contribute to future investigations of novel chemical scaffolds and the discovery of novel hits in high-throughput screening as potential anti-SARS-CoV-2 properties. Communicated by Ramaswamy H. Sarma Abstract : UF0001