One tactic for cysteine protease inhibition is to form a covalent bond between an electrophilic atom of the inhibitor and the thiol of the catalytic cysteine. In this study, we evaluate the reaction free energy obtained from a hybrid quantum mechanical/molecular mechanical (QM/MM) free energy profile as a predictor of affinity for reversible, covalent inhibitors of rhodesain. We demonstrate that the reaction free energy calculated with the PM6/MM potential is in agreement with the experimental data and suggest that the free energy profile for covalent bond formation in a protein environment may be a useful tool for the inhibitor design.

中文翻译：

---

评估半胱氨酸蛋白酶共价抑制剂的QM / MM自由能表面。

半胱氨酸蛋白酶抑制的一种策略是在抑制剂的亲电子原子和催化半胱氨酸的硫醇之间形成共价键。在这项研究中，我们评估了从混合量子力学/分子机械（QM / MM）自由能谱获得的反应自由能，作为对可逆性罗丹蛋白酶抑制剂的亲和力的预测指标。我们证明用PM6 / MM电位计算的反应自由能与实验数据一致，并表明在蛋白质环境中形成共价键的自由能谱可能是抑制剂设计的有用工具。