Structural modification of antineoplastic drug carmofur designed to the inhibition of SARS-CoV-2 main protease: A theoretical investigation

Niloofar Hemati; Saba Hadidi; Farshad Shiri; Mohammad Hosein Farzaei

doi:10.1016/j.rechem.2021.100259

Structural modification of antineoplastic drug carmofur designed to the inhibition of SARS-CoV-2 main protease: A theoretical investigation

Results Chem. 2022 Jan:4:100259. doi: 10.1016/j.rechem.2021.100259. Epub 2021 Dec 9.

Authors

Niloofar Hemati¹, Saba Hadidi², Farshad Shiri², Mohammad Hosein Farzaei³

Affiliations

¹ Internal Medicine Department, Kermanshah University of Medical Sciences, Kermanshah, Iran.
² Department of Inorganic Chemistry, Faculty of Chemistry, Razi University, Kermanshah, Iran.
³ Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.

Abstract

A coherent account of the reaction mechanistic details, structural modifications, and inhibition potentials of antineoplastic drug carmofur and its modified analogs to inhibition of SARS-CoV-2 main protease (M^pro) is reported. The survey is performed by integrating the density functional based tight binding (DFTB3) with density functional theory (DFT) calculations. The inhibition process commences with nucleophilic attack from the sulfur atom on the carbonyl group, yielding a C-S bond formation, followed by a bond formation of the H-O9 by 2.07 Å, which results in a transition state contains a ring of six atoms. We found that although the direct addition of sulfhydryl group hydrogen to the N3 position is likely to happen, the proper position of the hydrogen to O9 decreases its accessibility. The thermodynamic stability of the complex was calculated to be highly sensitive to the substituent on the N11 position. Compounds with CH₂NH₂ and CH₂F at N11 positions of carmofur revealed high thermodynamic stability to complexation with M^pro but induced no change in substrate-binding pocket comparable to carmofur. Replacing the N11 of carmofur with carbon (C-carmofur) was effective in terms of complexation stability at CH₂CH₂CH₂F and CH₂CH₂CH₂OH substitutions and occupation of S1 subsite by these structures in addition to the S2 subsite. Based on the resulted data, increasing the length of the carbon chain at introduced substitutions in N-carmofur almost decreases the complexation stability while in C-carmofur the trend is reversed. Throughout these information outputs, it was suggested that compounds d, e, i', and k' might be novel and more efficacious drug candidates instead of carmofur. We believe that our characterization of mechanistic details and structural modification on M^pro/carmofur complex will significantly intensify researchers' understanding of this system, and consequently help them to take advantage of results into practice and design various valuable derivatives for inhibition of SARS-CoV-2 main protease.

Keywords: Carmofur; SARS-CoV-2 main protease; Structural modification.