Identification of a potential SARS-CoV2 inhibitor via molecular dynamics simulations and amino acid decomposition analysis

Abstract

Considering lack of validated therapeutic drugs or vaccines against contagious SARS-CoV2, various efforts have been focused on repurposing of existing drugs or identifying new agents. In an attempt to identify new and potential SARS-CoV2 inhibitors targeting specific enzyme of the pathogen, a few induced fit models of SARS-CoV2 main protease (Mpro) including N-aryl amide and aryl sulfonamide based fragments were subjected to a multi-step in silico strategy. Sub-structure query of co-crystallographic fragments provided numerous ZINC15 driven commercially available compounds that entered molecular docking stage to find binding interactions/modes inside Mpro active site. Docking results were reevaluated through time dependent stability of top-ranked ligand-protease complexes by molecular dynamics (MD) simulations within 50 ns. Relative contribution of interacted residues in binding to the most probable binding pose was estimated through amino acid decomposition analysis in B3LYP level of theory with Def2-TZVPP split basis set. In confirmation of docking results, MD simulations revealed less perceptible torsional distortions (more stable binding mode) in binding of ZINC_252512772 (ΔG_b −9.18 kcal/mol) into Mpro active site. H-bond interactions and hydrophobic contacts were determinant forces in binding interactions of in silico hit. Quantum chemical calculations confirmed MD results and proved the pivotal role of a conserved residue (Glu166) in making permanent hydrogen bond (98% of MD simulations time) with ZINC_252512772. Drug-like physicochemical properties as well as desirable target binding interactions nominated ZINC_252512772 as a desirable in silico hit for further development toward SARS-CoV2 inhibitors.

Highlights

• A few N-aryl amide/aryl sulfonamide based fragments were subjected to a multi-step in silico strategy to afford potential SARS-CoV2 Mpro inhibitors.

• MD simulations revealed less perceptible torsional distortions (more stable binding mode) in binding of ZINC_252512772 (ΔG_b -9.18 kcal/mol) into Mpro active site.

• H-bond interactions and hydrophobic contacts were determinant forces in binding interactions of in silico hit.

• Quantum chemical calculations confirmed MD results and proved pivotal role of a conserved residue (Glu166) in making permanent hydrogen bond (98% of MD simulations time) with ZINC_252512772.

Communicated by Ramaswamy H. Sarma

Keywords:

• Covid-19
• main protease
• molecular dynamics
• in silico hit

A new pathogen (SARS-CoV2) that first emerged in Wuhan region of China in December 2019 spread quickly into all countries of the world. Given an urgent need toward therapeutic drugs or vaccines against the pathogen, seeking for new privileged anti-SARS-CoV2 molecules with good synthetic accessibility or commercial availability is now an important attitude for structure-based hit/lead generation. In the current study potential SARS-CoV2 inhibitors were proposed through in silico analysis of ZINC15 driven commercially available compounds against Mpro as the specific enzyme of pathogen with determinant role in maturation of viral nonstructural proteins (Nsps) and hence viral life cycle. For this purpose, a few co-crystallographic ligands of SARS-CoV2 Mpro with N-aryl amide and aryl sulfonamide based fragments were used to identify new and potential enzyme inhibitors via screening ZINC driven commercially available developed structures. Molecular docking simulations proposed ZINC_108126011 and ZINC_252512772 as superior Mpro binders with free binding energies comparable to a few re-purposed drugs. H-bond interactions and hydrophobic contacts were dominant attractive forces in binding to target. MD simulations on top-ranked docked poses demonstrated less conformational changes (more stable binding mode) for ZINC_252512772 within Mpro active site during 50 ns trajectory. Per-residue binding energy analysis of ZINC_252512772-Mpro complex determined relative contribution of individual interacted residues in binding to the selected hit. Quantum chemical calculations confirmed MD results and proved the pivotal role of Glu166 in making permanent hydrogen bond (98% of MD simulations time) with ZINC_252512772. Obtained results showed that ZINC_252512772 might be a desirable in silico hit for further development of potent SARS-CoV2 inhibitors. Although additional effort remains to be made for in vitro, in vivo and clinical validations, it is hoped that proposed compound could serve as appropriate hit molecules for further development of anti-Covid-19 agents.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the Ardabil University of Medical Sciences under Grant no. IR.ARUMS.REC.1399.002.