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

Samir Chtita; Salah Belaidi; Faizan Abul Qais; Mebarka Ouassaf; Muneerah Mogren AlMogren; Ateyah A Al-Zahrani; Mohamed Bakhouch; Assia Belhassan; Hanane Zaki; Mohammed Bouachrine; Tahar Lakhlifi

doi:10.1016/j.jksus.2022.102226

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

J King Saud Univ Sci. 2022 Oct;34(7):102226. doi: 10.1016/j.jksus.2022.102226. Epub 2022 Jul 20.

Authors

Affiliations

¹ Laboratory of Analytical and Molecular Chemistry of Sciences Ben M'Sik, Hassan II University of Casablanca, B.P. 7955 Sidi Othmane, Casablanca, Morocco.
² Laboratory of Molecular Chemistry and Environment, University of Biskra, BP145, 07000 Biskra, Algeria.
³ Pharmaceutical Sciences Research Center (CRSP), New City Ali Mendjeli, Constantine, Algeria.
⁴ Department of Agricultural Microbiology, Faculty of Agricultural Sciences, Aligarh Muslim University, Aligarh, UP 202002, India.
⁵ Department of Chemistry, Faculty of Sciences, King Saud University, Riyadh 11451, Saudi Arabia.
⁶ Chemical Engineering Department, College of Engineering, King Saud University, Riyadh 11451, Saudi Arabia.
⁷ Laboratory of Bioorganic Chemistry, Department of Chemistry, Faculty of Sciences, Chouaïb Doukkali University, P.O. Box 24, El Jadida M-24000, Morocco.
⁸ Molecular Chemistry and Natural Substances Laboratory, Faculty of Science, Moulay Ismail University, B.P. 11201 Zitoune, Meknes, Morocco.
⁹ Higher School of Technology Khenifra, Sultane Moulay Slimane University, Khenifra, Morocco.

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.

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