Division of Medicinal and Process Chemistry, Central Drug Research Institute, CSIR, Lucknow 226001, India.
J Med Chem. 2010 Sep 9;53(17):6490-505. doi: 10.1021/jm100573q.
A systematic virtual screening (VS) experiment, consisting of the development of 3D-pharmacophore, screening of virtual library, synthesis, and pharmacology, is reported. The predictive pharmacophore model (correlation = 0.955) with one H-bond donor and three hydrophobic features was developed using HypoGen on a training set of 24 carbamates as AChE inhibitors. The model was validated on a test set of 40 carbamates (correlation = 0.844). The pharmacophore-based VS of virtual library led to the identification of novel carbamates as potent AChE inhibitors. The synthesis and pharmacological evaluation of nine carbamates against three diverse assay systems, namely (i) in vitro Ellman method, (ii) in vivo passive avoidance test, and (iii) aldicarb-sensitivity assay, led to the discovery of orally active novel AChE inhibitors which improved scopolamine-induce cognition impairment in Swiss male mice. Finally, two novel lead compounds 85 and 86 are selected as candidate molecules for further optimization.
报道了一项系统的虚拟筛选（VS）实验，包括 3D 药效团的构建、虚拟库的筛选、合成和药理学研究。使用 HypoGen 在一组 24 个作为乙酰胆碱酯酶抑制剂的氨基甲酸酯训练集上开发了一个具有一个氢键供体和三个疏水特征的预测药效团模型（相关性=0.955）。该模型在 40 个氨基甲酸酯的测试集上进行了验证（相关性=0.844）。基于药效团的虚拟库 VS 导致了新型氨基甲酸酯作为有效的乙酰胆碱酯酶抑制剂的鉴定。对九种氨基甲酸酯针对三种不同的测定系统（即（i）体外 Ellman 法，（ii）体内被动回避试验，和（iii）硫代氨基甲酸酯敏感性试验）的合成和药理学评价，导致发现了具有口服活性的新型乙酰胆碱酯酶抑制剂，改善了瑞士雄性小鼠中东莨菪碱诱导的认知障碍。最后，选择了两个新型先导化合物 85 和 86 作为进一步优化的候选分子。
