Molecular Bio-Computation & Drug Design Lab, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4000, South Africa.
Université Cadi Ayyad, Faculté des Sciences Semlalia, Département de Chimie, Av. My Abdellah, BP2390 Marrakech, Morocco.
Future Med Chem. 2018 May 1;10(9):1003-1015. doi: 10.4155/fmc-2017-0275. Epub 2018 Apr 9.
Irreversible covalent drug inhibition is an emerging paradigm; however, critical gaps in unraveling the efficacy of molecular determinants still persist.
We compare two ERK2 inhibitors with different binding modes. A 5-7-Oxozeaenol is selective inhibitor which irreversibly binds ERK2 by the formation of covalent bond with Cys166 while 5-iodotubercidin binds noncovalently. Result & discussion: Covalent inhibition showed greater protein stability, favorable binding energetics (irreversible inhibition binding free energy [ΔG] = -40.4354 kcal/mol and reversible inhibition ΔG = -26.2515 kcal/mol); higher correlation in residual movement and multiple van der Waals interactions as evident from residue interaction analysis.
This investigation of the different inhibition modes of ERK2 would assist toward the design of more potent and highly site-specific covalent inhibitors in cancer therapy.
不可逆转的共价药物抑制是一种新兴的模式；然而，在揭示分子决定因素的疗效方面，仍存在一些关键的差距。
我们比较了两种具有不同结合模式的 ERK2 抑制剂。5-7-氧杂玉米黄质是一种选择性抑制剂，通过与半胱氨酸 166 形成共价键不可逆地结合 ERK2，而 5-碘尿苷则非共价结合。
共价抑制显示出更高的蛋白稳定性、有利的结合能（不可逆抑制结合自由能[ΔG] = -40.4354 kcal/mol，可逆抑制ΔG = -26.2515 kcal/mol）；从残基相互作用分析可以看出，残留运动和多个范德华相互作用的相关性更高。
对 ERK2 不同抑制模式的研究将有助于设计更有效和高度特异性的共价抑制剂，用于癌症治疗。
