The 3CL or main protease of SARS-CoV-2 contains a Cys-His catalytic dyad in the active site that performs the hydrolysis of peptide bonds at specific sites of the polyprotein chain obtained after translation of the genome of the virus in infected cells. This enzyme thus plays an essential role during the replication of the virus and has not closely related homologues in human beings, making it an attractive drug target. We have used a combination of classical and hybrid QM/MM Molecular Dynamics simulations to explore the reactivity of this enzyme and its inhibition with several compounds, including a Michael acceptor, an aldehyde and a ketone-based inhibitor. By means of the Adaptive String Method (<i>J. Phys. Chem. A</i> 2017, 121, 51, 9764–9772) we have been able to determine the multidimensional Minimum Free Energy Paths associated to the chemical reactions under study using a DFT description for the QM subsystem. The common picture obtained after our simulations is that the enzyme is activated after a proton transfer within the catalytic dyad to form an ion pair. From this state the reaction proceeds with the formation of covalent bond between the sulphur atom of the catalytic cysteine and a carbon atom of the substrate and a proton transfer from the catalytic histidine to a neighbor substrate position. The atomistic information obtained from these simulations could be useful to assist in the design of new inhibitors of the 3CL protease.

Computational analysis of catalysis and inhibition in SARS-CoV-2 3CL protease using DFT/MM free energy simulations

ACS Spring Meeting 2021

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