Identification of Drug Combination Therapies for SARS-CoV-2: A Molecular Dynamics Simulations Approach

Heba Abdel-Halim,1,*,† Malak Hajar1,†, Luma Hasouneh1,†, Suzanne MA Abdelmalek2,† 1Department of Medicinal Chemistry, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan; 2Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan†Dr Abdel-Halim passed away on July 14, 2022*These authors contributed equally to this workCorrespondence: Suzanne MA Abdelmalek, Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, P.O. Box 961343, Amman, 11196, Jordan, Tel +962-6-5799555 Ext. (8310), Fax +962-65715570, Email sabdelmalek@uop.edu.joPurpose: The development of effective treatments for coronavirus infectious disease 19 (COVID-19) caused by SARS-Coronavirus-2 was hindered by the little data available about this virus at the start of the pandemic. Drug repurposing provides a good strategy to explore approved drugs’ possible SARS-CoV-2 antiviral activity. Moreover, drug synergism is essential in antiviral treatment due to improved efficacy and reduced toxicity. In this work, we studied the effect of approved and investigational drugs on one of SARS-CoV-2 essential proteins, the main protease (Mpro), in search of antiviral treatments and/or drug combinations.Methods: Different possible druggable sites of Mpro were identified and screened against an in-house library of more than 4000 chemical compounds. Molecular dynamics simulations were carried out to explore conformational changes induced by different ligands’ binding. Subsequently, the inhibitory effect of the identified compounds and the suggested drug combinations on the Mpro were established using a 3CL protease (SARS-CoV-2) assay kit.Results: Three potential inhibitors in three different binding sites were identified; favipiravir, cefixime, and carvedilol. Molecular dynamics simulations predicted the synergistic effect of two drug combinations: favipiravir/cefixime, and favipiravir/carvedilol. The in vitro inhibitory effect of the predicted drug combinations was established on this enzyme.Conclusion: In this work, we could study one of the promising SARS-CoV-2 viral protein targets in searching for treatments for COVID-19. The inhibitory effect of several drugs on Mpro was established in silico and in vitro assays. Molecular dynamics simulations showed promising results in predicting the synergistic effect of drug combinations.Keywords: molecular dynamics simulations, ligand docking, multiple binding sites, drug synergy, SARS-CoV-2