Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4001, South Africa.
Chemistry Department, Faculty of Applied and Computer Science, Vanderbijlpark Campus, Vaal University of Technology, Vanderbijlpark 1900, South Africa.
Molecules. 2022 Jul 8;27(14):4372. doi: 10.3390/molecules27144372.
In over a century since its discovery, Alzheimer's disease (AD) has continued to be a global health concern due to its incurable nature and overwhelming increase among older people. In this paper, we give an overview of the efforts of researchers towards identifying potent BACE1 exosite-binding antibodies and allosteric inhibitors. Herein, we apply computer-aided drug design (CADD) methods to unravel the interactions of some proposed psychotic and meroterpenoid BACE1 allosteric site inhibitors. This study is aimed at validating the allosteric potentials of these selected compounds targeted at BACE1 inhibition. Molecular docking, molecular dynamic (MD) simulations, and post-MD analyses are carried out on these selected compounds, which have been experimentally proven to exhibit allosteric inhibition on BACE1. The SwissDock software enabled us to identify more than five druggable pockets on the BACE1 structural surface using docking. Besides the active site region, a melatonin derivative (compound ) previously proposed as a BACE1 allostery inhibitor showed appreciable stability at eight different subsites on BACE1. Refinement with molecular dynamic (MD) simulations shows that the identified non-catalytic sites are potential allostery sites for compound . The allostery and binding mechanism of the selected potent inhibitors show that the smaller the molecule, the easier the attachment to several enzyme regions. This finding hereby establishes that most of these selected compounds failed to exhibit strong allosteric binding with BACE1 except for compound . We hereby suggest that further studies and additional identification/validation of other BACE1 allosteric compounds be done. Furthermore, this additional allosteric site investigation will help in reducing the associated challenges with designing BACE1 inhibitors while exploring the opportunities in the design of allosteric BACE1 inhibitors.
自发现以来的一个多世纪以来，由于阿尔茨海默病（AD）无法治愈且在老年人中发病率极高，它一直是全球关注的健康问题。在本文中，我们概述了研究人员在识别强效 BACE1 外位结合抗体和别构抑制剂方面所做的努力。在此，我们应用计算机辅助药物设计（CADD）方法来揭示一些拟议的精神药物和倍半萜 BACE1 别构抑制剂的相互作用。本研究旨在验证这些针对 BACE1 抑制的选定化合物的别构潜力。对这些经实验证明对 BACE1 具有别构抑制作用的选定化合物进行了分子对接、分子动力学（MD）模拟和 MD 后分析。SwissDock 软件使我们能够使用对接在 BACE1 结构表面上识别出五个以上可成药口袋。除了活性位点区域之外，先前被提议为 BACE1 别构抑制剂的褪黑素衍生物（化合物 ）在 BACE1 的八个不同亚位点上表现出相当的稳定性。使用分子动力学（MD）模拟进行的细化表明，所识别的非催化位点是化合物 的潜在别构位点。所选有效抑制剂的别构和结合机制表明，分子越小，与几个酶区域的结合就越容易。这一发现表明，除了化合物 之外，这些选定的化合物大多数都未能与 BACE1 表现出强烈的别构结合。因此，我们建议进一步研究并鉴定其他 BACE1 别构化合物。此外，对其他 BACE1 别构化合物的进一步研究和鉴定将有助于在探索别构 BACE1 抑制剂设计机会的同时，减少设计 BACE1 抑制剂所面临的挑战。
