The inhibition mechanism of the main protease (M pro ) of SARS-CoV-2 by ebselen (EBS) and its analog with a hydroxyl group at position 2 of the benzisoselenazol-3(2H)-one ring (EBS-OH) was studied by using a density functional level of theory. Preliminary molecular dynamics simulations on the apo form of M pro were performed taking into account both the hydrogen donor and acceptor natures of the Nδ and Nε of His41, a member of the catalytic dyad. The potential energy surfaces for the formation of the Se–S covalent bond mediated by EBS and EBS-OH on M pro are discussed in detail. The EBS-OH shows a distinctive behavior with respect to EBS in the formation of the noncovalent complex. Due to the presence of canonical H-bonds and noncanonical ones involving less electronegative atoms, such as sulfur and selenium, the influence on the energy barriers and reaction energy of the Minnesota hybrid meta-GGA functionals M06, M06-2X and M08HX, and the more recent range-separated hybrid functional wB97X were also considered. The knowledge of the inhibition mechanism of M pro by the small protease inhibitors EBS or EBS-OH can enlarge the possibilities for designing more potent and selective inhibitor-based drugs to be used in combination with other antiviral therapies.
【저자키워드】 SARS-CoV-2 main protease, DFT, inhibition mechanism, Se–S covalent bond, potential energy surface, 【초록키워드】 SARS-CoV-2, knowledge, drug, molecular dynamics, protease, Molecular dynamics simulation, Protease inhibitor, Selenium, Ebselen, mechanism, Donor, Combination, antiviral therapies, hydrogen, potential energy, hydroxyl group, complex, M pro, position, member, catalytic dyad, His41, apo form, theory, selective, H-bond, sulfur, hydroxyl, covalent bond, performed, functional, less, canonical, 【제목키워드】 SARS-CoV-2, inhibition, bond, Formation,