No abstract

Cysteine proteases are the most abundant proteases in parasitic protozoa and they are essential enzymes to the life cycle of several of them, thus becoming attractive therapeutic targets for the development of new inhibitors. In this paper, a computational study of the inhibition mechanism of cysteine protease by dipeptidyl-2,3-epoxyketone Cbz-Phe-Hph-(S), a recently proposed inhibitor, has been carried out by means of molecular dynamics (MD) simulations with hybrid QM/MM potentials. The computed free energy surfaces of the inhibition mechanism of cysteine proteases by peptidyl epoxyketones showing how the activation of the epoxide ring and the attack of Cys25 on either C2 or C3 atoms take place in a concerted manner. According to our results, the acid species responsible for the protonation of the oxygen atom of the ring would be able to conserve His159, in contrast to previous studies that proposed a water molecule as the activating species. The low activation free energies for the reaction where Cys25 attacks the C2 atom of the epoxide ring (12.1 kcal mol) or to the C3 atom (15.4 kcal mol), together with the high negative reaction energies suggest that the derivatives of peptidyl-2,3-epoxyketones can be used to develop new potent inhibitors for the treatment of Chagas disease.

The SARS-CoV-2 main protease (M^pro) is essential for replication of the virus responsible for the COVID-19 pandemic, and one of the main targets for drug design. Here, we simulate the inhibition process of SARS-CoV-2 M^pro with a known Michael acceptor (peptidyl) inhibitor, N3. The free energy landscape for the mechanism of the formation of the covalent enzyme-inhibitor product is computed with QM/MM molecular dynamics methods. The simulations show a two-step mechanism, and give structures and calculated barriers in good agreement with experiment. Using these results and information from our previous investigation on the proteolysis reaction of SARS-CoV-2 M^pro, we design two new, synthetically accessible N3-analogues as potential inhibitors, in which the recognition and warhead motifs are modified. QM/MM modelling of the mechanism of inhibition of M^pro by these novel compounds indicates that both may be promising candidates as drug leads against COVID-19, one as an irreversible inhibitor and one as a potential reversible inhibitor.

No abstract

The SARS-CoV-2 main protease (M^pro) is essential for replication of the virus responsible for the COVID-19 pandemic, and one of the main targets for drug design. Here, we simulate the inhibition process of SARS-CoV-2 M^pro with a known Michael acceptor (peptidyl) inhibitor, N3. The free energy landscape for the mechanism of the formation of the covalent enzyme-inhibitor product is computed with QM/MM molecular dynamics methods. The simulations show a two-step mechanism, and give structures and calculated barriers in good agreement with experiment. Using these results and information from our previous investigation on the proteolysis reaction of SARS-CoV-2 M^pro, we design two new, synthetically accessible N3-analogues as potential inhibitors, in which the recognition and warhead motifs are modified. QM/MM modelling of the mechanism of inhibition of M^pro by these novel compounds indicates that both may be promising candidates as drug leads against COVID-19, one as an irreversible inhibitor and one as a potential reversible inhibitor.