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Computational studies on potential new anti-Covid-19 agents with a multi-target mode of action




doi: 10.1016/j.jksus.2022.102086.


Online ahead of print.

Affiliations

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Ranjan K Mohapatra et al.


J King Saud Univ Sci.


.

Abstract

A compound that could inhibit multiple targets associated with SARS-CoV-2 infection would prove to be a drug of choice against the virus. Human receptor-ACE2, receptor binding domain (RBD) of SARS-CoV-2 S-protein, Papain-like protein of SARS-CoV-2 (PLpro), reverse transcriptase of SARS-CoV-2 (RdRp) were chosen for in silico study. A set of previously synthesized compounds (1-5) were docked into the active sites of the targets. Based on the docking score, ligand efficiency, binding free energy, and dissociation constants for a definite conformational position of the ligand, inhibitory potentials of the compounds were measured. The stability of the protein-ligand (P-L) complex was validated in silico by using molecular dynamics simulations using the YASARA suit. Moreover, the pharmacokinetic properties, FMO and NBO analysis were performed for ranking the potentiality of the compounds as drug. The geometry optimizations and electronic structures were investigated using DFT. As per the study, compound-5 has the best binding affinity against all four targets. Moreover, compounds 1, 3 and 5 are less toxic and can be considered for oral consumption.


Keywords:

Drug-likeness prediction; Frontiers Molecular Orbital; Molecular docking; Molecular dynamics; Molecular electrostatic potential; Natural Bond Orbital; Pharmacokinetics; SARS-CoV-2.

Figures



Fig. 1

Molecular electrostatic potential (MEP) maps obtained for compounds 1-5 (a: denotes transparent display and b denotes solid display)


Fig. 2


Fig. 2

[EHOMO−ELUMO] energy band gaps obtained for compounds 1-5 (value in electron volt)


Fig. 3


Fig. 3

Natural Bond Orbital (NBO) plots obtained for compounds 1-5


Fig. 4


Fig. 4

Intermolecular interactions of compound 5 with (a) PLpro, (b) RdRp, (c) RBD, (d) ACE2


Fig. 5


Fig. 5

(a) RMSD in Å of the ligand movement of ACE2-5 (blue, avg. 3.753), RBD-5 (red, avg. 6.038), PLpro-5 (green, avg. 4.009), and RdRp-5 (brown, avg. 6.186) complexes during the MD simulations. (b) RMSD in Å of protein-ligand Cα trajectory of ACE2-5 (blue, avg. 1.728), RBD-5 (red, avg.1.319), PLpro-5 (green, avg. 2.715), and RdRp-5 (brown, avg. 1.809) complexes during the MD simulations.


Fig. 6


Fig. 6

Radius of gyration (Rg) in Å of ACE2-5 (blue, avg. 25.236), RBD-5 (red, avg. 18.435), PLpro-5 (green, avg. 18.435), and RdRp-5 (brown, 29.74) complexes during the MD simulations.

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