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

Sinthyia Ahmed, Rumana Mahtarin, Sayeda Samina Ahmed, Shaila Akter, Md. Shamiul Islam, Abdulla Al Mamun, Rajib Islam, Md Nayeem Hossain, Md Ackas Ali , Mossammad U. C. Sultana, MD. Rimon Parves, M. Obayed Ullah, Mohammad A. Halim

10.1080/07391102.2020.1796804

Research curated

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.

Source: PubMed

Related molecules

Name	Synonyms	Genes
Raltegravir
RNA dependent RNA polymerase	RDR, viral RNA polymerase, RdRp, nsp12	rep, ORF1a-1b, RdRp
Cobicistat
3C-like protease	3CLpro, Mpro, SARS coronavirus main peptidase, 3CLpro-SARS-CoV-2	rep, ORF1a-1b
Daclatasvir
Simeprevir	Olysio, TMC435350, TMC-435, TMC435

Related interactions

Target	Drug	Type	Result
3C-like protease	Raltegravir	Computational	positive
RNA dependent RNA polymerase	Simeprevir	Computational	positive
RNA dependent RNA polymerase	Cobicistat	Computational	positive
RNA dependent RNA polymerase	Daclatasvir	Computational	positive
3C-like protease	Daclatasvir	Computational	positive
3C-like protease	Cobicistat	Computational	positive
3C-like protease	Simeprevir	Computational	positive
RNA dependent RNA polymerase	Raltegravir	Computational	positive