Rutin and flavone analogs as prospective SARS-CoV-2 main protease inhibitors: In silico drug discovery study

Mahmoud A A Ibrahim; Eslam A R Mohamed; Alaa H M Abdelrahman; Khaled S Allemailem; Mahmoud F Moustafa; Ahmed M Shawky; Ali Mahzari; Abdulrahim Refdan Hakami; Khlood A A Abdeljawaad; Mohamed A M Atia

doi:10.1016/j.jmgm.2021.107904

Rutin and flavone analogs as prospective SARS-CoV-2 main protease inhibitors: In silico drug discovery study

J Mol Graph Model. 2021 Jun:105:107904. doi: 10.1016/j.jmgm.2021.107904. Epub 2021 Mar 20.

Affiliations

¹ Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia, 61519, Egypt. Electronic address: m.ibrahim@compchem.net.
² Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia, 61519, Egypt.
³ Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia.
⁴ Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia; Department of Botany & Microbiology, Faculty of Science, South Valley University, Qena, Egypt.
⁵ Science and Technology Unit (STU), Umm Al-Qura University, Makkah, 21955, Saudi Arabia.
⁶ Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Albaha University, Albaha, Saudi Arabia.
⁷ Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, 61481, Saudi Arabia.
⁸ Molecular Genetics and Genome Mapping Laboratory, Genome Mapping Department, Agricultural Genetic Engineering Research Institute (AGERI), Agricultural Research Center (ARC), Giza, 12619, Egypt. Electronic address: matia@ageri.sci.eg.

Abstract

Coronavirus disease 2019 (COVID-19) is a new pandemic characterized by quick spreading and illness of the respiratory system. To date, there is no specific therapy for Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). Flavonoids, especially rutin, have attracted considerable interest as a prospective SARS-CoV-2 main protease (M^pro) inhibitor. In this study, a database containing 2017 flavone analogs was prepared and screened against SARS-CoV-2 M^pro using the molecular docking technique. According to the results, 371 flavone analogs exhibited good potency towards M^pro with docking scores less than -9.0 kcal/mol. Molecular dynamics (MD) simulations, followed by molecular mechanics-generalized Born surface area (MM/GBSA) binding energy calculations, were performed for the top potent analogs in complex with M^pro. Compared to rutin, PubChem-129-716-607 and PubChem-885-071-27 showed better binding affinities against SARS-CoV-2 M^pro over 150 ns MD course with ΔG_binding values of -69.0 and -68.1 kcal/mol, respectively. Structural and energetic analyses demonstrated high stability of the identified analogs inside the SARS-CoV-2 M^pro active site over 150 ns MD simulations. The oral bioavailabilities of probable SARS-CoV-2 M^pro inhibitors were underpinned using drug-likeness parameters. A comparison of the binding affinities demonstrated that the MM/GBSA binding energies of the identified flavone analogs were approximately three and two times less than those of lopinavir and baicalein, respectively. In conclusion, PubChem-129-716-607 and PubChem-885-071-27 are promising anti-COVID-19 drug candidates that warrant further clinical investigations.

Keywords: COVID-19; Drug-likeness; Molecular docking; Molecular dynamics; SARS-CoV-2 main protease.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

COVID-19*
Drug Discovery
Flavones* / pharmacology
Humans
Molecular Docking Simulation
Prospective Studies
Protease Inhibitors
Rutin / pharmacology
SARS-CoV-2

Substances

Flavones
Protease Inhibitors
Rutin