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On the origin of the stereoselective affinity of Nutlin-3 geometrical isomers for the MDM2 protein

机译：关于Nutlin-3几何异构体对MDM2蛋白的立体选择性亲和力的起源

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摘要

The stereoselective affinity of small-molecule binding to proteins is typically broadly explained in terms of the thermodynamics of the final bound complex. Using Brownian dynamics simulations, we show that the preferential binding of the MDM2 protein to the geometrical isomers of Nutlin-3, an effective anticancer lead that works by inhibiting the interaction between the proteins p53 and MDM2, can be explained by kinetic arguments related to the formation of the MDM2:Nutlin-3 encounter complex. This is a diffusively bound state that forms prior to the final bound complex. We find that the MDM2 protein stereoselectivity for the Nutlin-3a enantiomer stems largely from the destabilization of the encounter complex of its mirror image enantiomer Nutlin-3b, by the K70 residue that is located away from the binding site. On the other hand, the trans-Nutlin-3a diastereoisomer exhibits a shorter residence time in the vicinity of MDM2 compared with Nutlin-3a due to destabilization of its encounter complex by the collective interaction of pairs of charged residues on either side of the binding site: Glu25 and Lys51 on one side, and Lys94 and Arg97 on the other side. This destabilization is largely due to the electrostatic potential of the trans-Nutlin-3a isomer being largely positive over extended continuous regions around its structure, which are otherwise well-identified into positive and negative regions in the case of the Nutlin-3a isomer. Such rich insight into the binding processes underlying biological selectivity complements the static view derived from the traditional thermodynamic analysis of the final bound complex. This approach, based on an explicit consideration of the dynamics of molecular association, suggests new avenues for kinetics-based anticancer drug development and discovery.
机译：小分子结合蛋白质的立体选择性亲和力通常根据最终结合的复合物的热力学来广泛解释。使用布朗动力学模拟，我们显示MDM2蛋白与Nutlin-3的几何异构体的优先结合，Nutlin-3是一种有效的抗癌药物，可通过抑制p53和MDM2蛋白之间的相互作用起作用，可以通过与MDM2：Nutlin-3的形成遇到复合物。这是在最终结合复合物之前形成的扩散结合状态。我们发现，对于Nutlin-3a对映体，MDM2蛋白的立体选择性很大程度上源于其镜像对映体Nutlin-3b的相遇复合物的失稳，其原因是远离结合位点的K70残基。另一方面，与Nutlin-3a相比，反式Nutlin-3a非对映异构体在MDM2附近表现出更短的停留时间，这是由于结合位点两侧带电残基对共同相互作用导致其相遇复合物不稳定而导致：一侧为Glu25和Lys51，另一侧为Lys94和Arg97。这种不稳定作用主要是由于反式Nutlin-3a异构体的静电势在围绕其结构的延伸连续区域上大都是正电，否则在Nutlin-3a异构体的情况下可以很好地识别为正负区域。对生物学选择性背后的结合过程的如此丰富的见解补充了从对最终结合复合物的传统热力学分析中得出的静态观点。该方法基于对分子缔合动力学的明确考虑，为基于动力学的抗癌药物开发和发现提供了新途径。

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