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 CH(2)NH(2) and CH(2)F 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 CH(2)CH(2)CH(2)F and CH(2)CH(2)CH(2)OH 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.