European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2010-01-14 , DOI: 10.1016/j.ejmech.2009.12.070 Reema Abu Khalaf , Ghassan Abu Sheikha , Yasser Bustanji , Mutasem O. Taha
Cholesteryl ester transfer protein (CETP) is involved in trafficking lipoprotein particles and neutral lipids between HDL and LDL and therefore is considered a valid target for treating dyslipidemic conditions and complications. Pharmacophore modeling and quantitative structure–activity relationship (QSAR) analysis were combined to explore the structural requirments for potent CETP inhibitors. Two pharmacophores emerged in the optimal QSAR equation (r2 = 0.800, n = 96, F = 72.1, r2LOO = 0.775, r2PRESS against 22 external test inhibitors = 0.707) suggesting the existence of at least two distinct binding modes accessible to ligands within CETP binding pocket. The successful pharmacophores were complemented with strict shape constraints in an attempt to optimize their receiver-operating characteristic (ROC) curve profiles.
The validity of our modeling approach was experimentally established by the identification of several CETP inhibitory leads retrieved via in silico screening of the National Cancer Institute (NCI) list of compounds and an in house built database of drugs and agrochemicals. Two hits illustrated low micromolar IC50 values: NSC 40331 (IC50 = 6.5 μM) and NSC 89508 (IC50 = 1.9 μM). Active hits were then used to guide synthetic exploration of a new series of CETP inhibitors.
中文翻译:
通过基于配体的药效团建模和QSAR分析,然后进行合成探索,发现了新的胆固醇酯转移蛋白抑制剂
胆固醇酯转移蛋白(CETP)参与在HDL和LDL之间转运脂蛋白颗粒和中性脂质,因此被认为是治疗血脂异常和并发症的有效靶点。结合了药理学模型和定量构效关系(QSAR)分析,探讨了强效CETP抑制剂的结构要求。在最佳QSAR方程中出现了两个药效基团(r 2 = 0.800,n = 96,F = 72.1,r 2 LOO = 0.775,r 2 PRESS相对于22种外部测试抑制剂= 0.707),表明存在至少两种不同的结合模式,可通过CETP结合口袋中的配体接近。成功的药效团辅以严格的形状限制,以优化其受体操作特性(ROC)曲线图。
我们的建模方法的有效性是通过鉴定通过计算机筛选国家癌症研究所(NCI)化合物清单以及内部建立的药物和农用化学品数据库检索到的几种CETP抑制性引线而建立的。两次命中显示出较低的微摩尔IC 50值:NSC 40331(IC 50 = 6.5μM)和NSC 89508(IC 50 = 1.9μM )。然后使用主动命中来指导新系列CETP抑制剂的合成探索。