Screening of Natural Products Targeting SARS-CoV-2–ACE2 Receptor Interface – A MixMD Based HTVS Pipeline

Abstract

The COVID-19 pandemic, caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a severe global health crisis now. SARS-CoV-2 utilizes its Spike protein receptor-binding domain (S-protein) to invade human cell through binding to Angiotensin-Converting Enzyme 2 receptor (ACE2). S-protein is the key target for many therapeutics and vaccines. Potential S-protein-ACE2 fusion inhibitor is expected to block the virus entry into the host cell. In many countries, traditional practices, based on natural products (NPs) have been in use to slow down COVID-19 infection. In this study, a protocol was applied that combines mixed solvent molecular dynamics simulations (MixMD) with high-throughput virtual screening (HTVS) to search NPs to block SARS-CoV-2 entry into the human cell. MixMD simulations were employed to discover the most promising stable binding conformations of drug-like probes in the S-protein-ACE2 interface. Detected stable sites were used for HTVs of 612093 NPs to identify molecules that could interfere with the S-protein-ACE2 interaction. In total, 19 NPs were selected with rescoring model. These top-ranked NP-S-protein complexes were subjected to classical MD simulations for 300 ns (3 replicates of 100 ns) to estimate the stability and affinity of binding. Three compounds, ZINC000002128789, ZINC000002159944 and SN00059335, showed better stability in all MD runs, of which ZINC000002128789 was predicted to have the highest binding affinity, suggesting that it could be effective modulator in RBD-ACE2 interface to prevent SARS-CoV-2 infection. Our results support that NPs may provide tools to fight COVID-19.

Screening S protein – ACE2 blockers from natural products: Strategies and advances in the discovery of potential inhibitors of COVID-19

“…It is a cosolvent simulation technique for identification of binding hots pots such as orthosteric, allosteric and cofactor binding sites as well as PPI sites [ 74 ]. Gopinath [ 75 ] used MixMD to detect potential inhibitor binding sites on S protein-ACE2 PPI interface. Drug-like organic probe molecules were added to the solvent to observe their localization in the simulation process, so as to detect the possible small molecule binding sites on the surface of S protein-ACE2 interface.…”

Inhibitory effects of specific combination of natural compounds against SARS-CoV-2 and its Alpha, Beta, Gamma, Delta, Kappa, and Mu variants

“…Application of natural compounds with their wide pleiotropic effects provides an opportunity of controlling several mechanisms associated with SARS-CoV-2 infection with a high margin of safety. Since the emergence of COVID-19, several studies have shown the efficacy of such compounds as inhibitors [14][15][16][17]. Our earlier studies also identified the efficacy of plant-derived compounds on several cellular mechanisms of SARS-CoV-2 infectivity [18][19][20].…”

Virtual screening and in vitro validation of natural compound inhibitors against SARS-CoV-2 spike protein

“…Most docking studies screening natural compounds against the spike protein have screened only a small number of ligands (≤200) and focus on the computational aspect alone [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] . Even larger-scale studies do not include experimental validation [41] , [42] , [43] . To address these limitations, we performed a structure-based docking study targeted at the regions of the spike receptor binding domain (RBD) involved in stabilisation of the Lys31 and Lys353 hotspots.…”