In Silico Identification and Analysis of Potentially Bioactive Antiviral Phytochemicals against SARS‐CoV‐2: A Molecular Docking and Dynamics Simulation Approach

Abstract

SARS-CoV-2, a deadly coronavirus sparked COVID-19 pandemic around the globe. With an increased mutation rate, this infectious agent is highly transmissible inducing an escalated rate of infections and death everywhere. Hence, the discovery of a viable antiviral therapy option is urgent. Computational approaches have offered a revolutionary framework to identify novel antimicrobial treatment regimens and allow a quicker, cost-effective, and productive conversion into the health center by evaluating preliminary and safety investigations. The primary purpose of this research was to find plausible plant-derived antiviral small molecules to halt the viral entrance into individuals by clogging the adherence of Spike protein with human ACE2 receptor and to suppress their genome replication by obstructing the activity of Nsp3 (Nonstructural protein 3) and 3CLpro (main protease). An in-house library of 1163 phytochemicals were selected from the NPASS and PubChem databases for downstream analysis. Preliminary analysis with SwissADME and pkCSM revealed 149 finest small molecules from the large dataset. Virtual screening using the molecular docking scoring and the MM-GBSA data analysis revealed that three candidate ligands CHEMBL503 (Lovastatin), CHEMBL490355 (Sulfuretin), and CHEMBL4216332 (Grayanoside A) successfully formed docked complex within the active site of human ACE2 receptor, Nsp3, and 3CLpro, respectively. Dual method molecular dynamics (MD) simulation and post-MD MM-GBSA further confirmed efficient binding and stable interaction between the ligands and target proteins. Furthermore, biological activity spectra and molecular target analysis revealed that all three preselected phytochemicals were biologically active and safe for human use. Throughout the adopted methodology, all three therapeutic candidates significantly outperformed the control drugs (Molnupiravir and Paxlovid). Finally, our research implies that these SARS-CoV-2 protein antagonists might be viable therapeutic options. At the same time, enough wet lab evaluations would be needed to ensure the therapeutic potency of the recommended drug candidates for SARS-CoV-2.

Identification of Phytochemicals from Arabian Peninsula Medicinal Plants as Strong Binders to SARS-CoV-2 Proteases (3CLPro and PLPro) by Molecular Docking and Dynamic Simulation Studies

“…These interactions contributed substantially to the binding potential of compounds 1-10 with 3CL Pro . The non-covalent interaction of compounds 1-10 with 3CL Pro is in agreement with some recent studies in which phytochemicals and herbal medicines have also shown their preferential binding with catalytic dyads that led to the inhibition of 3CL Pro activity in SARS-CoV-2 [29,54,55]. In addition, we found that compounds 2, 3, and 10 showed high negative docking scores (−7.7, −8.0, and −8.2 kcal/mol), which are comparable to the Remdesivir-3CL Pro docking score (−8.2 kcal/mol) [56].…”

In Silico Antiviral Drug Repurposing Against COVID‐19 Infection: Targeting the Main Protease and Human ACE2 Receptor

“…When we compare these scores to existing research using commercial drugs like Paxlovid and molnupiravir, we see that the docking scores with respect to Mpro are −6.4 and −6.6 kcal/mol, while for the ACE2 receptor, it is −7.6 and −7 kcal/mol, respectively. It′s clear that the docking scores for our predicted compounds are lower than those previous scores [45,46] . Figure 3 (a & b) Shows the best docked pose of CoV2 main protease and ACE2 receptor with corresponding antiviral drugs.…”

Immunoinformatics, molecular docking and dynamics simulation approaches unveil a multi epitope-based potent peptide vaccine candidate against avian leukosis virus

“…The process primarily based on multiple factors such as detection of hydrophobic or hydrophilic interactions, salt bridges and electrostatic and hydrogen bonding interactions. The computed atlas of surface topography of proteins (CASTp 3.0) website ( http://sts.bioe.uic.edu/castp/index.html?3igg ) was exploited to determine the vaccine’s active regions 60 , 61 . The default probe radius of 1.4 ˚A was used.…”