Kaur Rajdeep, Narang Simranjeet Singh, Singh Pritpal, Goyal Bhupesh
Department of Chemistry, Faculty of Basic and Applied Sciences, Sri Guru Granth Sahib World University, Fatehgarh Sahib, Punjab, India.
School of Chemistry & Biochemistry, Thapar Institute of Engineering & Technology, Patiala, Punjab, India.
J Biomol Struct Dyn. 2023;41(22):13211-13227. doi: 10.1080/07391102.2023.2191722. Epub 2023 Apr 4.
Amyloid-β (Aβ) aggregation and β-amyloid precursor protein cleaving enzyme 1 (BACE1) are the potential therapeutic drug targets for Alzheimer's disease (AD). A recent study highlighted that tacrine-benzofuran hybrid C1 displayed anti-aggregation activity against Aβ peptide and inhibit BACE1 activity. However, the inhibition mechanism of C1 against Aβ aggregation and BACE1 activity remains unclear. Thus, molecular dynamics (MD) simulations of Aβ monomer and BACE1 with and without C1 were performed to inspect the inhibitory mechanism of C1 against Aβ aggregation and BACE1 activity. In addition, a ligand-based virtual screening followed by MD simulations was employed to explore potent new small-molecule dual inhibitors of Aβ aggregation and BACE1 activity. MD simulations highlighted that C1 promotes the non aggregating helical conformation in Aβ and destabilizes D23-K28 salt bridge that plays a vital role in the self-aggregation of Aβ. C1 displays a favourable binding free energy (-50.7 ± 7.3 kcal/mol) with Aβ monomer and preferentially binds to the central hydrophobic core (CHC) residues. MD simulations highlighted that C1 strongly interacted with the BACE1 active site (Asp32 and Asp228) and active pockets. The scrutiny of interatomic distances among key residues of BACE1 highlighted the close flap (non-active) position in BACE1 on the incorporation of C1. The MD simulations explain the observed high inhibitory activity of C1 against Aβ aggregation and BACE1 in the studies. The ligand-based virtual screening followed by MD simulations identified CHEMBL2019027 (C2) as a promising dual inhibitor of Aβ aggregation and BACE1 activity.Communicated by Ramaswamy H. Sarma.
淀粉样β蛋白（Aβ）聚集和β-淀粉样前体蛋白裂解酶1（BACE1）是阿尔茨海默病（AD）潜在的治疗药物靶点。最近一项研究强调，他克林-苯并呋喃杂合物C1对Aβ肽具有抗聚集活性，并能抑制BACE1活性。然而，C1对Aβ聚集和BACE1活性的抑制机制仍不清楚。因此，进行了有或没有C1存在时Aβ单体和BACE1的分子动力学（MD）模拟，以研究C1对Aβ聚集和BACE1活性的抑制机制。此外，采用基于配体的虚拟筛选并结合MD模拟，来探索强效的新型Aβ聚集和BACE1活性双小分子抑制剂。MD模拟表明，C1促进Aβ形成非聚集螺旋构象，并使在Aβ自聚集过程中起关键作用的D23-K28盐桥不稳定。C1与Aβ单体表现出良好的结合自由能（-50.7±7.3千卡/摩尔），并优先结合到中央疏水核心（CHC）残基上。MD模拟表明，C1与BACE1活性位点（Asp32和Asp228）及活性口袋强烈相互作用。对BACE1关键残基间原子距离的仔细研究表明，加入C1后BACE1的瓣片（非活性）处于关闭位置。MD模拟解释了在这些研究中观察到的C1对Aβ聚集和BACE1的高抑制活性。基于配体的虚拟筛选并结合MD模拟，确定了CHEMBL2019027（C2）是一种有前景的Aβ聚集和BACE1活性双抑制剂。由拉马斯瓦米·H·萨尔马传达。
