<br/>The 3CL or main protease of SARS-CoV-2 is an essential enzyme for the replication cycle of the virus. This enzyme has not closely related homologues in human beings and it is well conserved among different coronaviruses, making it an attractive drug target. We have investigated the covalent inhibition of the 3CL protease with compounds that contain different warheads. We employed a combination of QM/MM methods and multidimensional free energy path determination to establish the reaction mechanisms and to calculate the free energy change associated to covalent inhibition. We also used alchemical free energy transformationd to suggest possible improvements of the proposed inhibitors.

Multiscale simulations of SARS-CoV-2 3CL protease covalent inhibition: Reaction mechanisms and design

ACS Fall 2021

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