On leave from Laboratório de Planejamento e Desenvolvimento de Fármacos, Universidade Federal do Pará, Rua Augusto Correa S/N, 66075-110, Belém, PA, Brazil.
Phys Chem Chem Phys. 2019 Nov 28;21(44):24723-24730. doi: 10.1039/c9cp04820k. Epub 2019 Nov 4.
Nitrile reversible covalent inhibitors of human cathepsin L (hCatL) bind covalently to the side chain of the catalytic Cys25 residue in the S1 pocket to form thioimidates. Predicting the binding of reversible covalent inhibitors is essential for their practical application in drug design. In this report, five nitrile-based inhibitors coded Neq0570, Neq0710, Neq0802, Neq0803 and Neq0804 had their hCatL inhibition constants, K, determined. These analogs of the prototypical Neq0570 are halogenated reversible covalent inhibitors of hCatL, which bear a halogen atom in the meta position of the P3 benzyl ring that can form a halogen bond with the Gly61 of the hCatL. To describe halogen bonding interaction in an inhibitor-hCatL complex, we applied an extra point (EP) of charge to represent the anisotropic distribution of charge on the iodine, bromine and chlorine atoms. Besides, we have used alchemical free energy calculations for evaluating the overall relative binding free energies of these inhibitors using a two-state binding model: noncovalent and covalent bond states. Our results show that free energy perturbation (FEP) can predict the hCatL binding affinities of halogenated reversible covalent inhibitors in close agreement with experiments.
Nitrile 可逆共价抑制剂的人组织蛋白酶 L (hCatL) 绑定共价侧链的催化 Cys25 残基在 S1 口袋形成硫代亚氨。预测可逆共价抑制剂的结合对于它们在药物设计中的实际应用是至关重要的。在本报告中，五个基于腈的抑制剂编码 Neq0570，Neq0710，Neq0802，Neq0803 和 Neq0804 有其 hCatL 抑制常数，K，测定。这些类似物的原型 Neq0570 是卤代可逆共价抑制剂的 hCatL，其在 P3 苄基环的间位带有卤原子，该卤原子可以与 hCatL 的 Gly61 形成卤键。为了描述抑制剂-hCatL 复合物中的卤键相互作用，我们应用了一个额外的点 (EP) 的电荷来表示碘、溴和氯原子上电荷的各向异性分布。此外，我们已经使用了自由能计算来评估这些抑制剂的整体相对结合自由能，使用两态结合模型：非共价和共价键状态。我们的研究结果表明，自由能扰动 (FEP) 可以预测卤代可逆共价抑制剂与实验非常吻合的 hCatL 结合亲和力。
