Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, 160 062 Punjab, India.
Bioorg Med Chem Lett. 2011 Feb 15;21(4):1105-12. doi: 10.1016/j.bmcl.2010.12.131. Epub 2011 Jan 1.
Dual binding site acetylcholinesterase (AChE) inhibitors are promising for the treatment of Alzheimer's disease (AD). They alleviate the cognitive deficits and AD-modifying agents, by inhibiting the β-amyloid (Aβ) peptide aggregation, through binding to both the catalytic and peripheral anionic sites, the so called dual binding site of the AChE enzyme. In this Letter, chemical features based 3D-pharmacophore models were developed based on the eight potent and structurally diverse AChE inhibitors (I-VIII) obtained from high-throughput in vitro screening technique. The best 3D-pharmacophore model, Hypo1, consists of two hydrogen-bond acceptor lipid, one hydrophobe, and two hydrophobic aliphatic features obtained by Catalyst/HIPHOP algorithm adopted in Discovery studio program. Hypo1 was used as a 3D query in sequential virtual screening study to filter three small compound databases. Further, a total of nine compounds were selected and followed on in vitro analysis. Finally, we identified two leads--Specs1 (IC(50)=3.279 μM) and Spec2 (IC(50)=5.986 μM) dual binding site compounds from Specs database, having good AChE enzyme inhibitory activity.
双结合位点乙酰胆碱酯酶（AChE）抑制剂有望用于治疗阿尔茨海默病（AD）。它们通过与 AChE 酶的两个结合位点（即催化和外周阴离子位点）结合，抑制β-淀粉样肽（Aβ）的聚集，从而减轻认知缺陷和 AD 修饰剂。在这封信中，基于从高通量体外筛选技术获得的八种有效且结构多样的 AChE 抑制剂（I-VIII），开发了基于化学特征的 3D 药效团模型。最佳 3D 药效团模型 Hypo1 由 Catalyst/HIPHOP 算法在 Discovery studio 程序中采用的两个氢键受体脂、一个疏水基和两个疏水脂肪特征组成。Hypo1 被用作顺序虚拟筛选研究中的 3D 查询，以筛选三个小分子化合物数据库。进一步，选择了总共 9 种化合物并进行了体外分析。最后，我们从 Specs 数据库中鉴定出两种具有良好乙酰胆碱酯酶抑制活性的双结合位点化合物 Spec1（IC50=3.279 μM）和 Spec2（IC50=5.986 μM）。
