Investigating the binding affinity, interaction, and structure-activity-relationship of 76 prescription antiviral drugs targeting RdRp and Mpro of SARS-CoV-2

Abstract

SARS-CoV-2 virus outbreak poses a major threat to humans worldwide due to its highly contagious nature. In this study, molecular docking, molecular dynamics, and structure-activity relationship are employed to assess the binding affinity and interaction of 76 prescription drugs against RNA dependent RNA polymerase (RdRp) and Main Protease (Mpro) of SARS-CoV-2. The RNA-dependent RNA polymerase is a vital enzyme of coronavirus replication/transcription complex whereas the main protease acts on the proteolysis of replicase polyproteins. Among 76 prescription antiviral drugs, four drugs (Raltegravir, Simeprevir, Cobicistat, and Daclatasvir) that are previously used for human immunodeficiency virus (HIV), hepatitis C virus (HCV), Ebola, and Marburg virus show higher binding energy and strong interaction with active sites of the receptor proteins. To explore the dynamic nature of the interaction, 100 ns molecular dynamics (MD) simulation is performed on the selected protein-drug complexes and apo-protein. Binding free energy of the selected drugs is performed by MM/PBSA. Besides docking and dynamics, partial least square (PLS) regression method is applied for the quantitative structure activity relationship to generate and predict the binding energy for drugs. PLS regression satisfactorily predicts the binding energy of the effective antiviral drugs compared to binding energy achieved from molecular docking with a precision of 85%. This study highly recommends researchers to screen these potential drugs in vitro and in vivo against SARS-CoV-2 for further validation of utility.

The FDA-approved drug cobicistat synergizes with remdesivir to inhibit SARS-CoV-2 replication

“…Additional in-silico investigation of the binding poses of cobicistat to the 3CLpro of SARS-CoV-2 corroborated the potential affinity of this drug 3CLpro ( Figure 1A,B). Moreover, our results were in line with similar independent analyses of other groups (43)(44)(45) We then tested the effect of cobicistat on SARS-CoV-2 replication in vitro. For this purpose, we conducted a time course analysis of the effect of different concentrations of cobicistat on intracellular viral RNA replication and release of virus into the culture supernatant of Calu-3 cells (Figure 1C-E; Supplementary Figure 1A,B).…”

Hepatitis C Virus Protease Inhibitors Show Differential Efficacy and Interactions with Remdesivir for Treatment of SARS-CoV-2 in Vitro

“…It should be noted that simeprevir was also described to impact cellular innate immune responses 61 and that alternative viral targets, including nsp3 (papain like protease domain), nsp12 (polymerase), nsp13 (helicase), nsp14 (exonuclease and methyltransferase), nsp15 (endoribonuclease), nsp16 (2’-o-ribose methyltransferase), as well as structural proteins N (capsid) and Spike, were suggested for paritaprevir, grazoprevir and simeprevir by modelling studies. 53,67,78–82 Future detailed molecular studies are required to fully define the viral targets of different HCV PI.…”

Structure and dynamics of membrane protein in SARS-CoV-2

“…The existent variability in the MD trajectory was observed by different multivariate energy factors in the low-dimensional space (De Jong, 1990 ; Wold et al., 1987 ). The centering and scaling were executed for data pre-processing (Ahmed, Mahtarin, et al., 2020 ; Chowdhury et al., 2020 ). In the analysis, final 90 ns MD trajectories were utilized to reveal the variations among the model structures.…”