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An Insight into the Interaction Between α-Ketoamide-Based Inhibitor and Coronavirus Main Protease: A Detailed in Silico Study

submitted on 11.08.2020 and posted on 11.08.2020 by Snehasis Banerjee

The search for therapeutic drugs that can neutralize the effects of COVID-2019 (SARS-CoV-2) infection is the main focus of current research. The coronavirus main protease (Mpro) is an attractive target for anti-coronavirus drug design. Further, α-ketoamide is proved to be very effective as a reversible covalent-inhibitor against cysteine proteases. Herein, we report on the non-covalent to the covalent adduct formation mechanism of α‑ketoamide-based inhibitor with the enzyme active site amino acids by QM/SQM model (QM= quantum mechanical, SQM= semi-empirical QM). To uncover the mechanism, we focused on two approaches: a concerted and a stepwise fashion. The concerted pathway proceeds via deprotonation of the thiol of cysteine (here, Cys145 SgH) and simultaneous reversible nucleophilic attack of sulfur onto the α-ketoamide warhead. In this work, we propose three plausible concerted pathways. On the contrary, in a traditional two-stage pathway, the first step is proton transfer from Cys145 SgH to His41 Nd forming an ion pair, and consecutively, in the second step, the thiolate ion attacks the a-keto group to form a thiohemiketal. In this reaction, we find that the stability of the tetrahedral intermediate oxyanion/hydroxyl hole plays an important role. Moreover, as the α-keto group has two faces Si or Re for the nucleophilic attack, we considered both possibilities of attack leading to S- and R-thiohemiketal. We computed the structural, electronic, and energetic parameters of all stationary points including transition states via ONIOM methodology at B3LYP/6-31G(d):PM6 level. Furthermore, to get more accurate results, we also calculated the single-point dispersion-corrected energy profile by using ωB97X-D/6-31G(d,p):PM6 level. Additionally, to characterize covalent, weak noncovalent interaction (NCI) and hydrogen-bonds, we applied NCI-reduced density gradient (NCI-RDG) methods along with Bader’s Quantum Theory of Atoms-in-Molecules (QTAIM) and natural bonding orbital (NBO) analysis.


Email Address of Submitting Author


Government College of Engineering and Leather Technology



ORCID For Submitting Author


Declaration of Conflict of Interest

The authors declare no competing financial interest.

Version Notes

first time