PDF(Pubmed)
Abstract：
The inhibition mechanism of the main protease (Mpro) 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 Mpro 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 Mpro 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 Mpro 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.
摘要：
利用密度泛函理论水平研究了ebselen(EBS)及其类似物对SARS-CoV-2的主要蛋白酶(Mpro)的抑制机理,在苯并异硒唑-3(2H)-一环(EBS-OH)的2位具有羟基。考虑到催化二元体成员His41的Nδ和Nε的氢供体和受体性质，对Mpro的apo形式进行了初步的分子动力学模拟。详细讨论了Mpro上EBS和EBS-OH介导的Se-S共价键形成的势能面。EBS-OH在形成非共价复合物时显示出相对于EBS的独特行为。由于存在规范的H键和涉及较少电负性原子的非规范的H键，如硫和硒，对明尼苏达州混合元GGA功能M06，M06-2X和M08HX的能垒和反应能的影响，并且还考虑了最近的范围分离的混合功能wB97X。小蛋白酶抑制剂EBS或EBS-OH对Mpro的抑制机制的认识可以扩大设计更有效和选择性的基于抑制剂的药物以与其他抗病毒疗法组合使用的可能性。
