Prospects for the structure‒function evolution of SARS-CoV-2 main protease inhibitors

Abstract

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become the third case of widespread coronavirus infection. Together with the other two viruses, the SARS-CoV-2 virus is highly pathogenic, and some strains have a mortality rate of more than 1%. Moreover, it has become clear that coronaviruses mutate quite often, which reduces the effectiveness of available vaccines and forces the regular creation of new ones. The main viral protease M^pro is a suitable target for direct-acting drugs. Currently, there is only one recommended anticoronavirus drug, nirmatrelvir, which, however, does not have all the properties necessary for widespread and effective use. Thus, the development of a highly selective and effective protease inhibitor that can be taken orally still remains relevant. In this work, we performed an in-depth literature review of M^pro inhibitor studies and conducted extensive molecular dynamics simulations of M^pro-inhibitor complexes with computational prediction of binding ability and ADME (absorption, distribution, metabolism and excretion) properties of new compounds. On the basis of the literature review we composed a set of criteria that a potent inhibitor must meet. Then we created a set of possible inhibitors and their parts, which presumably allows all the necessary properties, namely, high affinity for the viral enzyme, selectivity, bioavailability and solubility, to be achieved.