a Laboratory of Biocrystallography and Computational Molecular Biology, Department of Physics , Periyar University , Salem 636 011 , Tamil Nadu , India.
J Biomol Struct Dyn. 2019 Jun;37(9):2339-2354. doi: 10.1080/07391102.2018.1479661. Epub 2018 Nov 19.
Alzheimer disease (AD) is a cruel neurodegenerative disorder caused by the deposition of amyloid β (Aβ) peptide inside the brain. The β-secretase (beta amyloid precursor protein (APP) cleaving enzyme 1, BACE1) is one of the enzymes involved in the cleavage of APP that leads to the Aβ formation and it is the primary target for the treatment of AD. Recent report outlines that verubecestat molecule strongly inhibits BACE1; however, its structure, binding mechanism and the stability in the active site of BACE1 are not yet known. The present study aims to determine the structure, binding affinity and the stability of verubecestat molecule in the active site of BACE1 from the molecular docking, quantum mechanics/molecular mechanics (QM/MM)-based charge density analysis and molecular dynamics simulation. Verubecestat molecule was docked at BACE1; it shows high binding affinity towards BACE1. Further, the conformational geometry and the intermolecular interactions of verubecestat in the active site of BACE1 were determined. The molecule forms strong interaction with the neighboring amino acids in the active site of BACE1. The onsite QM/MM-based charge density analysis reveals the nature of charge density distribution and the topological properties of intermolecular interactions of verubecestat molecule in the active site of BACE1. The calculated electrostatic potential (ESP) of verubecestat in the active site of BACE1 displays high negative and positive ESP regions of the molecule. This onsite QM/MM analysis is more relevant to the physiological situation. The molecular dynamics simulation has been performed, which confirms the high stability and compactness of verubecestat in the active site of BACE1. The MM-generalized Born surface area and MM-Poisson Boltzmann surface area free energy calculations of verubecestat-BACE1 also confirm the high binding affinity of verubecestat. Communicated by Ramaswamy H. Sarma.
阿尔茨海默病（AD）是一种由大脑内淀粉样 β（Aβ）肽沉积引起的残酷神经退行性疾病。β-分泌酶（β淀粉样前体蛋白（APP）裂解酶 1，BACE1）是参与 APP 裂解导致 Aβ形成的酶之一，是 AD 治疗的主要靶点。最近的报告概述了 verubecestat 分子强烈抑制 BACE1；然而，其结构、结合机制和 BACE1 活性部位的稳定性尚不清楚。本研究旨在通过分子对接、基于量子力学/分子力学（QM/MM）的电荷密度分析和分子动力学模拟，确定 verubecestat 分子在 BACE1 活性部位的结构、结合亲和力和稳定性。verubecestat 分子在 BACE1 上进行对接；它显示出对 BACE1 的高结合亲和力。此外，还确定了 verubecestat 在 BACE1 活性部位的构象几何形状和分子间相互作用。该分子与 BACE1 活性部位的相邻氨基酸形成强烈相互作用。现场 QM/MM 基于电荷密度分析揭示了 verubecestat 分子在 BACE1 活性部位的电荷密度分布和分子间相互作用的拓扑性质。verubecestat 在 BACE1 活性部位的计算静电势（ESP）显示出分子的高负电和正电 ESP 区域。这种现场 QM/MM 分析更符合生理情况。进行了分子动力学模拟，证实了 verubecestat 在 BACE1 活性部位的高稳定性和紧凑性。verubecestat-BACE1 的 MM-广义 Born 表面积和 MM-泊松 Boltzmann 表面面积自由能计算也证实了 verubecestat 的高结合亲和力。由 Ramaswamy H. Sarma 传达。
