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Abstract：
A good understanding of the inhibition mechanism of enzymes exhibiting high levels of similarity is the first step to the discovery of new drugs with selective potential. Examples of such proteins include glycogen synthase kinase-3 (GSK-3β) and cyclin-dependent kinase 2 (CDK-2). This article reports the mechanism of such enzyme inhibition as analyzed by an indoline sulfamylophenyl derivative (CHEMBL410072). Previous work has shown that such compounds exhibit selective properties towards their biological targets. This study used a combined procedure involving docking and molecular dynamics simulations, which allowed identification of interactions responsible for stabilization of complexes, and analysis of the dynamic stability of the systems obtained. The initial data obtained during the molecular docking stage show that the ligand molecule exhibits a similar affinity towards both active sites, which was confirmed by quantification of identified interactions and energy values. However, the data do not cover dynamic aspects of the considered systems. Molecular dynamics simulations realized for both complexes indicate significant dissimilarities in dynamics properties of both side chains of the considered ligands, especially in the case of the part containing the sulfamide group. Such increased mobility of the analyzed systems disrupts the stability of binding in the stabilized complex with GSK-3β protein, which finally affects also the binding affinity of the ligand molecule towards this enzyme.
摘要：
对表现出高度相似性的酶的抑制机制的良好理解是发现具有选择性潜力的新药的第一步。此类蛋白质的实例包括糖原合酶激酶-3(GSK-3β)和细胞周期蛋白依赖性激酶2(CDK-2)。本文报道了通过二氢吲哚磺氨基苯衍生物（CHEMBL410072）分析的这种酶抑制的机理。先前的工作已经表明,此类化合物对其生物靶标表现出选择性性质。这项研究使用了涉及对接和分子动力学模拟的组合程序，这允许识别负责复合物稳定的相互作用，并分析了所得系统的动态稳定性。在分子对接阶段获得的初始数据表明，配体分子对两个活性位点表现出相似的亲和力，这通过确定的相互作用和能量值的量化得到了证实。然而,数据不包括所考虑系统的动态方面。两种配合物的分子动力学模拟表明，所考虑的配体的两个侧链的动力学特性存在显着差异。特别是在含有磺酰胺基团的部分的情况下。所分析系统的这种增加的移动性破坏了与GSK-3β蛋白的稳定复合物结合的稳定性。这最终也影响配体分子对该酶的结合亲和力。
