Evaluation of apigenin-based biflavonoid derivatives as potential therapeutic agents against viral protease (3CLpro) of SARS-CoV-2 via molecular docking, molecular dynamics and quantum mechanics studies

Abstract

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of the pandemic COVID-19 disease that affects human respiratory function. Despite the scientific progression made in the development of the vaccine, there is an urgent need for the discovery of antiviral drugs for better performance at different stages of SARS-CoV-2 reproduction. The main protease (Mpro or 3CLpro) plays a pivotal role in the life cycle of the virus, making it an attractive target for the development of antiviral agents effective against the new strains of coronaviruses (CoVs). In this study, a series of apigenin-based natural biflavonoid derivatives as potential inhibitors of coronaviruses 3CLpro was investigated by in silico approaches. For this purpose, the molecular docking was performed to analyze the interaction of the natural biflavonoids with SARS-Cov-2 main protease and for further investigation, docking to the 3CLpro of SARS-CoV and MERS-CoV. Based on docking scores and comparison with the reference inhibitors (ritonavir and lopinavir), more than half of the biflavonoids had strong interactions with the residues of the binding pocket of the coronaviruses 3CLpro and exhibited better binding affinities toward the main protease than ritonavir and lopinavir. The top biflavonoids were further explored through molecular dynamics simulation, binding free energy calculation and residual energy contributions estimated by the MM-PBSA. Also, drug likeness property investigation by Swiss ADME tools and density functional theory (DFT) calculations were performed. The results confirmed that the 3CLpro-amentoflavone, 3CLpro-bilobetin, 3CLpro-ginkgetin, and 3CLpro-sotetsuflavone complexes possess a large amount of dynamic properties such as high stability, significant binding energy and fewer conformation fluctuations. Also, the pharmacokinetics and drug-likeness studies and HOMO-LUMO and DFT descriptor values indicated a promising result of the selected natural biflavonoids. Overall findings indicate that the apigenin-based biflavonoids may inhibit COVID-19 by significant interactions in the binding pocket and those results can pave the way in drug discovery although the effectiveness of these bioactive compounds should be further validated by in-vitro and in-vivo investigations.Communicated by Ramaswamy H. Sarma.

Keywords: Biflavonoids; Density functional theory; Main protease; Molecular docking; Molecular dynamics; SARS-CoV-2.