Preferability of Molnupiravir, an Anti-COVID-19 Drug, toward Purine Nucleosides: A Quantum Mechanical Study

Mahmoud A A Ibrahim; Mohammed N I Shehata; Nayra A M Moussa; Randa R A Hemia; Heba S M Abd Elhafez; Mohamed K Abd El-Rahman; Shaban R M Sayed; Peter A Sidhom; Eslam Dabbish; Tamer Shoeib

doi:10.1021/acsomega.3c03215

Preferability of Molnupiravir, an Anti-COVID-19 Drug, toward Purine Nucleosides: A Quantum Mechanical Study

ACS Omega. 2023 Jul 18;8(30):27553-27565. doi: 10.1021/acsomega.3c03215. eCollection 2023 Aug 1.

Authors

Affiliations

¹ Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia 61519, Egypt.
² School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4000, South Africa.
³ Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United States.
⁴ Department of Botany and Microbiology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.
⁵ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt.
⁶ Department of Chemistry, The American University in Cairo, New Cairo 11835, Egypt.

Abstract

Structural aspects of molnupiravir complexed with the RNA of the SARS-CoV-2 virus have been recently resolved inside the RNA-dependent RNA polymerase (RdRp), demonstrating the interactions of molnupiravir with purine nucleosides. However, the preference of molnupiravir to interact with one purine nucleoside over another has not been clearly investigated. Herein, the complexation of molnupiravir in its active form with guanosine and adenosine was compared, using sundry density functional theory calculations. The plausible tautomeric structures of the molnupiravir drug in complex with guanosine/adenosine were minutely scrutinized. The relative energy findings outlined the favorability of amino-molnupiravir···keto-amino-guanosine and imino-molnupiravir···amino-adenosine optimized complexes. According to the interaction (E_int) and binding (E_bind) energy values, higher preferential base-pairing of molnupiravir with guanosine over the adenosine one was recognized with E_int/E_bind values of -31.16/-21.81 and -13.93/-12.83 kcal/mol, respectively. This could be interpreted by the presence of three and two hydrogen bonds within the former and latter complexes, respectively. Observable changes in the electronic properties and global indices of reactivity of the studied complexes also confirmed the preferential binding within the studied complexes. The findings from the quantum theory of atoms in molecules and the noncovalent interaction index also support the partially covalent nature of the investigated interactions. For both complexes, changes in thermodynamic parameters outlined the spontaneous, exothermic, and nonrandom states of the inspected interactions. Inspecting the solvent effect on the studied interactions outlined more observable amelioration within the water medium compared with the gas one. These results would be a durable ground for the forthcoming studies concerned with the interactions of the molnupiravir drug with purine nucleosides.