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 (DG b À9.18 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 (DG 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.

Synthesis of Copper(II) Coordination Complex, Its Molecular Docking and Computational Exploration for Novel Functional Properties: A Dual Approach

“…Chloroquine (CQ) and Hydroxychloroquine (HCQ) are aminoquinolines, a class of heterocyclic scaffolds with an amino group. They can form metal complexes with Fe(II), Ni(II), Zn(II) and Cu(II) ions as an inhibitor for COVID‐19 [24–26] . Recently, our lab has synthesized several novel metal complexes possing good optoelectronic properties [10–12] .…”

“…They can form metal complexes with Fe(II), Ni(II), Zn(II) and Cu(II) ions as an inhibitor for COVID-19. [24][25][26] Recently, our lab has synthesized several novel metal complexes possing good optoelectronic properties. [10][11][12] Unlike the previous several studies, we have synthesized a novel copper (II) complex [Cu(phen) 3 ].…”

Identification of 1,2,3-triazole-phthalimide derivatives as potential drugs against COVID-19: a virtual screening, docking and molecular dynamic study

“…Our results showed that Autodock program was able to generate a successful pose (RMSD = 1.9 Å) ( Figure S6 ). It is assumed that scored poses with an RMSD of less 2.0 Å are considered to be successful (Bordogna et al, 2011; Razzaghi-Asl et al, 2020 ).…”

“…Molecular docking was performed based on the confrontation between optimized ligands structure and biomacromolecules from SARS-CoV-2. The crystal structure of viral proteins was obtained from the Protein Data Bank (PDB) under the codes: spike: 6VSB, in its open (6VYB) and closed states (6VXX) (Walls et al, 2020 ; Wrapp et al, 2020 ); nucleocapsid protein, 6VYO (Yadav et al, 2020 ) and M pro , 5R80 (Razzaghi-Asl et al, 2020 ). The validation of target protein-ligand complex structures was performed using the co-crystallized standard ligand of target proteins to ensure the virtual screening process.…”

A computational study of the interface interaction between SARS-CoV-2 RBD and ACE2 from human, cat, dog and ferret.

“…In this sense, evaluate this process from an atomistic point of view can provide important information about the role of these specific residues and the use of in silico strategies to simulate the interaction of proteins is ubiquitous, mainly using molecular docking and molecular dynamics simulations, since the advance of both hardware and software has allowed the study of bigger and larger systems 15 . In the case of the pandemic of the new coronavirus, molecular docking and classical molecular simulation are used in the some works to evaluate different aspects of the virus [16][17][18] . Considering the specific differences in the ACE2, we performed homology modeling, molecular docking and molecular dynamics simulations to observe the behavior of the interaction interface involving the RBD and ACE2 proteins for human, cat, dog, and ferret systems and, this is, as far we know, the first study of this kind.…”