Identification of antiviral phytochemicals as a potential SARS-CoV-2 main protease (Mpro) inhibitor using docking and molecular dynamics simulations

Abstract

Novel SARS-CoV-2, an etiological factor of Coronavirus disease 2019 (COVID-19), poses a great challenge to the public health care system. Among other druggable targets of SARS-Cov-2, the main protease (Mpro) is regarded as a prominent enzyme target for drug developments owing to its crucial role in virus replication and transcription. We pursued a computational investigation to identify Mpro inhibitors from a compiled library of natural compounds with proven antiviral activities using a hierarchical workflow of molecular docking, ADMET assessment, dynamic simulations and binding free-energy calculations. Five natural compounds, Withanosides V and VI, Racemosides A and B, and Shatavarin IX, obtained better binding affinity and attained stable interactions with Mpro key pocket residues. These intermolecular key interactions were also retained profoundly in the simulation trajectory of 100 ns time scale indicating tight receptor binding. Free energy calculations prioritized Withanosides V and VI as the top candidates that can act as effective SARS-CoV-2 Mpro inhibitors.

Computational molecular interaction between SARS-CoV-2 main protease and theaflavin digallate using free energy perturbation and molecular dynamics

“…Microbial natural products were also screened using molecular docking and dynamics for 20 ns [ 59 ]. Similarly, phytochemicals were also screened using docking, dynamics for 100 ns, and binding free energy estimation using MMPBSA [ 60 ]. 251 quantum mechanically optimized natural polyphenols were also studied using molecular docking and dynamics.…”

In Silico Analysis Using SARS-CoV-2 Main Protease and a Set of Phytocompounds to Accelerate the Development of Therapeutic Components against COVID-19

“…Several studies using bioinformatics and cheminformatics methodologies are being conducted to identify the inhibitors of SARS-CoV-2 M pro [53][54][55]. Many studies on the SARS-CoV-2 proteins focus on natural and phytocompounds [56][57][58]. Wetlab investigations are an unavoidable aspect of discovering the best lead compounds, though in silico studies generate substantial data.…”

Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2

“…Other natural product sources screened by docking and MM/PB­(GB)­SA against Mpro were flavonoid-based phytochemical constituents of calendula officinalis, phytochemicals in Indian ginseng, food compounds, marine natural polyketides, malaria-box compounds, cressa cretica compounds, strychnos nux-vomica products, ayurvedic compounds, moringa oleifera compounds, withania sp. products, stilbenolignans from plants, acridinedione analogs, alkaloids from justicia adhatoda , tea plant products, neem compounds, turmeric compounds, echinacea angustifolia products, Withania somnifera (ashwagandha) products, cyperus rotundus Linn products, salvia plebeia products, lichen compounds, curcuma longa products, and polyphenols from broussonetia papyrifera . − …”