Abstract：
We investigate the inhibition mechanism between pomotrelvir and the SARS-CoV-2 main protease using molecular mechanics and quantum mechanics / molecular mechanics simulations. Alchemical transformations where each Pi group of pomotrelvir was transformed into its counterpart in nirmatrelvir were performed to unravel the individual contribution of each group to the binding and reaction processes. We have shown that while a γ-lactam ring is preferred at position P1, a δ-lactam ring is a reasonable alternative. For the P2 position, tertiary amines are preferred with respect to secondary amines. Flexible side chains at P2 position can disrupt the preorganization of the active site, favouring the exploration of non-reactive conformations. The substitution of the P2 group of pomotrelvir by that of nirmatrelvir resulted in a compound, named as C2, that presents better binding free energy and a higher population of reactive conformations in the Michaelis complex. Analysis of the chemical reaction to form the covalent complex has shown a similar reaction mechanism and activation free energies for pomotrelvir, nirmatrelvir and C2. We hope that these findings could be useful to design better inhibitors to fight present and future variants of SARS-CoV-2 virus.
摘要：
我们使用分子力学和量子力学/分子力学模拟研究了pomotrelvir与SARS-CoV-2主要蛋白酶之间的抑制机制。进行炼金术转化，其中将每个Pi组的pomotrelvir转化为其在nirmatrelvir中的对应物，以阐明每个组对结合和反应过程的贡献。我们已经表明,虽然γ-内酰胺环在P1位是优选的,但δ-内酰胺环是合理的选择。对于P2位置，相对于仲胺,优选叔胺。P2位置的柔性侧链可以破坏活性位点的预组织，有利于探索非反应构象。将p2组的pomotrevir替换为nirmatrelvir,命名为C2，在Michaelis复合物中具有更好的结合自由能和更高的反应构象。形成共价复合物的化学反应的分析显示了类似的反应机理和活化自由能，nirmatrelvir和C2。我们希望这些发现可能有助于设计更好的抑制剂来对抗SARS-CoV-2病毒的当前和未来变体。
