Jana Srabanti, Ganeshpurkar Ankit, Singh Sushil Kumar
Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University) Varanasi-221005 India
RSC Adv. 2018 Nov 26;8(69):39477-39495. doi: 10.1039/c8ra08198k. eCollection 2018 Nov 23.
Ligand-based and energy-optimized structure-based approaches were considered to obtain excellent candidates as AChE inhibitors. The known AChE inhibitors were utilized to develop a pharmacophore hypothesis, HPRRR and X-ray crystallographic structures of AChE were used to produce three e-pharmacophore hypotheses . AHHRR, AHRR, and DHRR. Based on approaches, we came across eight structurally diverse hits as non-competitive AChE inhibitors with good ADME properties. The best four hits, ZINC20592007, ZINC05354646, ZINC20649934, and ZINC39154782 were non-toxic, neuroprotective, and were selective AChE inhibitors (IC values 482 ± 1.88 nM, 580 ± 1.63 nM, 854 ± 2.65 nM, and 636 ± 1.79 nM respectively). The hits showed non-competitive inhibition of AChE at PAS site with attractive values (0.21 ± 0.027 μM, 0.27 ± 0.064 μM, 0.3 ± 0.018 μM, and 0.28 ± 0.032 μM for ZINC20592007, ZINC05354646, ZINC20649934, and ZINC39154782 respectively), and increased the cholinergic activity as well as inhibited Aβ aggregation.
基于配体和能量优化的基于结构的方法被认为可获得作为乙酰胆碱酯酶（AChE）抑制剂的优秀候选物。利用已知的AChE抑制剂来建立药效团假设，AChE的HPRRR和X射线晶体学结构被用于生成三个电子药效团假设，即AHHRR、AHRR和DHRR。基于这些方法，我们发现了八种结构多样的命中物，它们作为具有良好药物代谢动力学（ADME）性质的非竞争性AChE抑制剂。最佳的四个命中物，即ZINC20592007、ZINC05354646、ZINC20649934和ZINC39154782是无毒的、具有神经保护作用的，并且是选择性AChE抑制剂（IC值分别为482±1.88 nM、580±1.63 nM、854±2.65 nM和636±1.79 nM）。这些命中物在PAS位点对AChE表现出非竞争性抑制，具有吸引人的解离常数（ZINC20592007、ZINC05354646、ZINC20649934和ZINC39154782分别为0.21±0.027 μM、0.27±0.064 μM、0.3±0.0
