Structural Basis of Potential Inhibitors Targeting SARS-CoV-2 Main Protease

Abstract

The Coronavirus disease-19 (COVID-19) pandemic is still devastating the world causing significant social, economic, and political chaos. Corresponding to the absence of globally approved antiviral drugs for treatment and vaccines for controlling the pandemic, the number of cases and/or mortalities are still rising. Current patient management relies on supportive treatment and the use of repurposed drugs as an indispensable option. Of a crucial role in the viral life cycle, ongoing studies are looking for potential inhibitors to the main protease (Mpro) of severe acute respiratory syndrome Coronavirus -2 (SARS-CoV-2) to tackle the pandemic. Although promising results have been achieved in searching for drugs inhibiting the Mpro, work remains to be done on designing structure-based improved drugs. This review discusses the structural basis of potential inhibitors targeting SARS-CoV-2 Mpro, identifies gaps, and provides future directions. Further, compounds with potential Mpro based antiviral activity are highlighted.

Potent Molecular Feature-based Neutralizing Monoclonal Antibodies as Promising Therapeutics Against SARS-CoV-2 Infection

“…Possible treatments against SARS-CoV-2 might also consist of a NmAbs-based cocktail combined with the currently used antivirals for treating COVID-19 patients. Interestingly, Mengist et al ( Mengist et al, 2020a ) highlighted the fact that the use of α-ketoamide inhibitors against SARS-CoV-2 M pro efficiencily block the COVID-19 progression, and that further researches on inhibitors targeting SARS-CoV-2 main protease might constitute attracting way to tackle COVID-19 ( Mengist et al, 2020a ; Mengist et al, 2020b ; Mohammad et al, 2020 ; Mengist et al, 2021 ). Thus, combination of these potential drugs with NmAbs might highly eradicated the pandemics due to coronavirus.…”

Discovery of SARS-CoV-2 MproPeptide Inhibitors from Modelling Substrate and Ligand Binding

“…In both the explicit-solvent MD and iMD-VR simulations, all 11 substrates are primarily held in place by stable backbone-backbone HBs (numbered 2, 3, 10 and 11 in Figure 3), involving M pro Glu-166 at S3 (2, 3) and Thr-26 at S2ʹ (10,11). Both residues consistently form significant contact interactions and energy contributions (vide infra).…”

“…4 Although no clinically approved M pro drugs are available, several small molecule inhibitors and peptidomimetics have been designed to inhibit SARS-CoV M pro and more recently SARS-CoV-2 M pro . 9,10 Indeed, a covalently-reacting M pro inhibitor from Pfizer has recently entered clinical trials. 11,12…”

In Silico Characterization of Masitinib Interaction with SARS‐CoV‐2 Main Protease

“…Our MD simulation results suggest that the N ‐benzylpiperazine portion of MST1 may not be essential for MST1‐M pro complex stability. Furthermore, none of the M pro inhibitors reported to date occupy the methylpiperazine site, which means that this M pro region does not play an essential role during inhibition [20] . Therefore, we made two modifications to the N ‐benzylpiperazine moiety of MST1 to support this hypothesis.…”