Original article
Unsymmetrical aromatic disulfides as SARS-CoV-2 Mpro inhibitors: Molecular docking, molecular dynamics, and ADME scoring investigations

https://doi.org/10.1016/j.jksus.2022.102226Get rights and content
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Abstract

COVID-19 pandemic caused by very severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) agent is an ongoing major global health concern. The disease has caused more than 452 million affected cases and more than 6 million death worldwide. Hence, there is an urgency to search for possible medications and drug treatments. There are no approved drugs available to treat COVID-19 yet, although several vaccine candidates are already available and some of them are listed for emergency use by the world health organization (WHO). Identifying a potential drug candidate may make a significant contribution to control the expansion of COVID-19. The in vitro biological activity of asymmetric disulfides against coronavirus through the inhibition of SARS-CoV-2 main protease (Mpro) protein was reported. Due to the lack of convincing evidence those asymmetric disulfides have favorable pharmacological properties for the clinical treatment of Coronavirus, in silico evaluation should be performed to assess the potential of these compounds to inhibit the SARS-CoV-2 Mpro.

In this context, we report herein the molecular docking for a series of 40 unsymmetrical aromatic disulfides as SARS-CoV-2 Mpro inhibitor. The optimal binding features of disulfides within the binding pocket of SARS-CoV-2 endoribonuclease protein (Protein Data Bank [PDB]: 6LU7) was described. Studied compounds were ranked for potential effectiveness, and those have shown high molecular docking scores were proposed as novel drug candidates against SARS-CoV-2. Moreover, the outcomes of drug similarity and ADME (Absorption, Distribution, Metabolism, and Excretion) analyses have may have the effectiveness of acting as medicines, and would be of interest as promising starting point for designing compounds against SARS-CoV-2. Finally, the stability of these three compounds in the complex with Mpro was validated through molecular dynamics (MD) simulation, in which they displayed stable trajectory and molecular properties with a consistent interaction profile.

Abbreviations

COVID-19
coronavirus disease 2019
SARS-CoV-2
severe acute respiratory syndrome coronavirus-2
WHO
World Health Organization
Mpro
Main protease
PDB
Protein Data Bank
SMILES
simplified molecular input line entry system
CYP
cytochrome P450
MD
molecular dynamics
RMSD
root-mean-square deviation
RMSF
root-mean-square fluctuation
Rg
radius of gyration
SASA
solvent-accessible surface area
HBD
hydrogen bond donor
HBA
hydrogen bond acceptor
RB
rotatable bond count
PSA
polar surface area

Keywords

COVID-19
SARS-CoV-2
Disulfides
Molecular docking
Molecular dynamics
Main protease

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Peer review under responsibility of King Saud University.