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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >A series of molecular modeling techniques to reveal selective mechanisms of inhibitors to beta-Site amyloid precursor protein cleaving enzyme 1 (BACE1) and beta-site amyloid precursor protein cleaving enzyme 2 (BACE2)
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A series of molecular modeling techniques to reveal selective mechanisms of inhibitors to beta-Site amyloid precursor protein cleaving enzyme 1 (BACE1) and beta-site amyloid precursor protein cleaving enzyme 2 (BACE2)

机译：一系列分子建模技术，以揭示抑制剂对β-位点淀粉样蛋白前体蛋白裂解酶1（BACE1）和β-位点淀粉样蛋白前体蛋白裂解酶2（Bace2）的选择机制

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Inhibition of beta-Site amyloid precursor protein cleaving enzyme 1 (BACE1) has been shown to be an effective treatment for Alzheimer's disease. A wealth of research has focused on finding highly selective small-molecule inhibitors targeting the BACE1 over its close homologue BACE2 to avoid potential side effects. However, given the highly structural similarities of BACE1 and BACE2, designing highly selective BACE1 inhibitors remains a huge challenge. Recently, it has been reported that a potential BACE1 inhibitor named C28 (similar to 52-fold selectivity) exhibited greater selectivity to BACE1 over BACE2 than the previously reported inhibitors AZD3293 and AZD3839 (similar to 1.5-fold and 14-fold selectivity). However, few computational studies have been performed to reveal its underlying mechanisms. In this study, a series of molecular modeling techniques were performed to reveal the selective mechanisms. Classical molecular dynamics (cMD) simulations indicated that the major variations appeared to be controlled by overall protein dynamics. Free energy calculations further suggested that the binding affinities of AZD3293 to BACE1 and BACE2 are similar, but the binding affinity of AZD3839 and C28 to BACE1 is much higher than to BACE2, and that the major variations are electrostatic interactions. The protein dynamics and energy differences were further observed in accelerated molecular dynamics (aMD) simulations. In addition, the umbrella sampling simulations revealed the inhibitors' different patterns of dissociation from the binding pockets of BACE1 and BACE2, and that different energy barriers were responsible for the selectivity. The physical principles revealed by this study may facilitate the rational design of more potent BACE1 selective inhibitors. Communicated by Ramaswamy H. Sarma
机译：抑制β位点淀粉样前体蛋白裂解酶1（BACE1）已被证明是治疗阿尔茨海默病的有效方法。大量研究集中于寻找针对BACE1的高选择性小分子抑制剂，而不是其近同源物BACE2，以避免潜在的副作用。然而，鉴于BACE1和BACE2的高度结构相似性，设计高选择性的BACE1抑制剂仍然是一个巨大的挑战。最近，有报道称，与之前报道的抑制剂AZD3293和AZD3839（类似于1.5倍和14倍的选择性）相比，一种名为C28的潜在BACE1抑制剂（类似于52倍的选择性）对BACE1的选择性高于BACE2。然而，很少有计算研究揭示其潜在机制。在这项研究中，一系列的分子模拟技术被用来揭示选择性机制。经典分子动力学（cMD）模拟表明，主要的变异似乎是由整体蛋白质动力学控制的。自由能计算进一步表明，AZD3293与BACE1和BACE2的结合亲和力相似，但AZD3839和C28与BACE1的结合亲和力远高于BACE2，主要变化是静电相互作用。在加速分子动力学（aMD）模拟中进一步观察到了蛋白质动力学和能量差异。此外，伞式取样模拟揭示了抑制剂从BACE1和BACE2结合囊中解离的不同模式，并且不同的能量屏障负责选择性。本研究揭示的物理原理可能有助于更有效的BACE1选择性抑制剂的合理设计。由拉玛斯瓦米·H·萨尔玛传达

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