The overexpression of p21-activated kinase 4 (PAK4) is associated with a variety of cancers. In this paper, the binding modes and inhibitory mechanisms of four 7H-pyrrolo[2,3-d]pyrimidine competitive inhibitors of PAK4 were investigated at the molecular level, mainly using molecular dynamics simulations and binding free energy calculations. The results show that the inhibitors had strong interactions with the hinge region, the β-sheets, and the residues with charged side chains around the 4-substituent. The terminal amino group of the inhibitor 5n was different from the other three, which could cause the enhancement of hydrogen bonds or electrostatic interactions formed with the surrounding residues. Thus, inhibitor 5n had the strongest inhibition capacity. The different halogen atoms on the 2-substituents of the inhibitors 5h, 5g, and 5e caused differences in the positions of the 2-benzene rings and affected the interactions of the hinge region. It also affected to some extent the orientations of the 4-imino groups and consequently their affinities for the surrounding charged residues. The combined results lead to the weakest inhibitory capacity of inhibitor 5e.

中文翻译：

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通过分子动力学模拟研究 7H-吡咯并 [2,3-d] 嘧啶衍生物作为 P21 激活激酶 4 抑制剂的抑制机制。

p21 活化激酶 4 (PAK4) 的过度表达与多种癌症有关。本文主要利用分子动力学模拟和结合自由能计算，在分子水平上研究了四种7H-吡咯并[2,3-d]嘧啶竞争性PAK4抑制剂的结合模式和抑制机制。结果表明，抑制剂与铰链区、β-折叠和 4-取代基周围带电荷侧链的残基有很强的相互作用。抑制剂5n的末端氨基不同于其他三个，这可能导致氢键增强或与周围残基形成的静电相互作用。因此，抑制剂5n具有最强的抑制能力。抑制剂5h、5g、2-取代基上的不同卤素原子 和 5e 引起 2-苯环位置的差异并影响铰链区的相互作用。它还在一定程度上影响了 4-亚氨基的方向，从而影响了它们对周围带电残基的亲和力。综合结果导致抑制剂 5e 的抑制能力最弱。