Laboratório de Planejamento e Desenvolvimento de Fármacos, Universidade Federal do Pará, Rua Augusto Correa S/N, 66075-110 Belém, PA, Brazil.
Laboratório de Química Quântica Computacional, Universidade Federal do Maranhão, 65080 401 São Luis, MA, Brazil.
J Chem Inf Model. 2022 Sep 12;62(17):4083-4094. doi: 10.1021/acs.jcim.2c00466. Epub 2022 Aug 31.
We have used molecular dynamics (MD) simulations with hybrid quantum mechanics/molecular mechanics (QM/MM) potentials to investigate the reaction mechanism for covalent inhibition of cathepsin K and assess the reversibility of inhibition. The computed free energy profiles suggest that a nucleophilic attack by the catalytic cysteine on the inhibitor warhead and proton transfer from the catalytic histidine occur in a concerted manner. The results indicate that the reaction is more strongly exergonic for the alkyne-based inhibitors, which bind irreversibly to cathepsin K, than for the nitrile-based inhibitor odanacatib, which binds reversibly. Gas-phase energies were also calculated for the addition of methanethiol to structural prototypes for a number of warheads of interest in cysteine protease inhibitor design in order to assess electrophilicity. The approaches presented in this study are particularly applicable to assessment of novel warheads, and computed transition state geometries can be incorporated into molecular models for covalent docking.
我们使用混合量子力学/分子力学（QM/MM）势能的分子动力学（MD）模拟来研究半胱氨酸蛋白酶 K 的共价抑制反应机制，并评估抑制作用的可逆性。计算得到的自由能曲线表明，催化半胱氨酸对抑制剂弹头的亲核攻击和催化组氨酸的质子转移以协同方式发生。结果表明，对于与半胱氨酸蛋白酶 K 不可逆结合的炔烃基抑制剂，反应的放热程度大于可可逆结合的腈基抑制剂odanacatib。还计算了一些感兴趣的半胱氨酸蛋白酶抑制剂设计的弹头结构原型与甲硫醇加成的气相能，以评估亲电性。本研究中提出的方法特别适用于新型弹头的评估，并且计算得到的过渡态几何形状可以被纳入共价对接的分子模型中。
