Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban, South Africa.
Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.
J Biomol Struct Dyn. 2022 Aug;40(12):5253-5265. doi: 10.1080/07391102.2020.1869099. Epub 2021 Jan 7.
β-amyloid precursor protein cleaving enzyme1 (BACE1) has prominently been an important drug design target implicated in Alzheimer's disease pathway. The failure rate of most of the already tested drugs at different clinical phases remains a major concern. Recently, AM-6494 was reported as a novel potent, highly selective, and orally effective inhibitor against BACE1. AM-6494 displayed no alteration of skin/fur colour in animal studies, an adverse effect common to previous BACE1 inhibitors. However, the atomistic molecular mechanism of BACE1 inhibition by AM-6494 remains unclear. To elucidate the binding mechanism of AM-6494 relative to umibecestat (CNP-520) as well as the structural changes when bound to BACE1, advanced computational techniques such as accelerated MD simulation and principal component analysis have been utilised. The results demonstrated higher binding affinity of AM-6494 at BACE1 with van der Waals as dominant energy contributor compared to umibecestat. Conformational monitoring of the β-hairpin flap covering the active site revealed an effective flap closure when bound with AM-6494 compared to CNP-520, which predominantly alternates between semi-open and closed conformations. The observed effective flap closure of AM-6494 explains its higher inhibitory power towards BACE1. Besides the catalytic Asp32/228 dyad, Tyr14, Leu30, Tyr71 and Gly230 represent critical residues in the potency of these inhibitors at BACE1 binding interface. The findings highlighted in this research provide a basis to explain AM-6494 high inhibitory potency and might assist in the design of new inhibitors with improved selectivity and potency for BACE1.
β-淀粉样前体蛋白裂解酶 1（BACE1）一直是阿尔茨海默病途径中重要的药物设计靶点。大多数已经在不同临床阶段测试的药物的失败率仍然是一个主要关注点。最近，AM-6494 被报道为一种新型有效的、高度选择性的、口服有效的 BACE1 抑制剂。AM-6494 在动物研究中没有改变皮肤/毛发颜色，这是以前 BACE1 抑制剂的常见不良反应。然而，AM-6494 抑制 BACE1 的原子分子机制尚不清楚。为了阐明 AM-6494 与 umibecestat（CNP-520）相对于 BACE1 的结合机制以及与 BACE1 结合时的结构变化，利用了加速 MD 模拟和主成分分析等先进的计算技术。结果表明，与 umibecestat 相比，AM-6494 在 BACE1 上具有更高的结合亲和力，范德华力是主要的能量贡献者。对覆盖活性位点的β发夹瓣的构象监测表明，与 CNP-520 相比，当与 AM-6494 结合时，发夹瓣有效地关闭，而 CNP-520 主要在半开和关闭构象之间交替。观察到 AM-6494 的有效发夹瓣关闭解释了其对 BACE1 的更高抑制能力。除了催化的 Asp32/228 二联体外，Tyr14、Leu30、Tyr71 和 Gly230 代表这些抑制剂在 BACE1 结合界面上的效力的关键残基。本研究中强调的发现为解释 AM-6494 高抑制效力提供了基础，并可能有助于设计具有更高选择性和效力的新型 BACE1 抑制剂。
