Swaan P W, Szoka F C, Oie S
Department of Biopharmaceutical Sciences, University of California, San Francisco 94143-0446, USA.
J Comput Aided Mol Des. 1997 Nov;11(6):581-8. doi: 10.1023/a:1007919704457.
A structure-binding activity relationship for the intestinal bile acid transporter has been developed using data from a series of bile acid analogs in a comparative molecular field analysis (CoMFA). The studied compounds consisted of a series of bile acid-peptide conjugates, with modifications at the 24 position of the cholic acid sterol nucleus, and compounds with slight modifications at the 3, 7, and 12 positions. For the CoMFA study, these compounds were divided into a training set and a test set, comprising 25 and 5 molecules, respectively. The best three-dimensional quantitative structure-activity relationship model found rationalizes the steric and electrostatic factors which modulate affinity to the bile acid carrier with a cross-validated, conventional and predictive r2 of 0.63, 0.96, and 0.69, respectively, indicating a good predictive model for carrier affinity. Binding is facilitated by positioning an electronegative moiety at the 24-27 position, and also by steric bulk at the end of the side chain. The model suggests substitutions at positions 3, 7, 12, and 24 that could lead to new substrates with reasonable affinity for the carrier.
利用一系列胆汁酸类似物的数据，通过比较分子场分析（CoMFA）建立了肠道胆汁酸转运体的结构-结合活性关系。所研究的化合物包括一系列胆汁酸-肽缀合物，它们在胆酸甾核的24位有修饰，以及在3、7和12位有轻微修饰的化合物。对于CoMFA研究，这些化合物被分为一个训练集和一个测试集，分别包含25个和5个分子。所发现的最佳三维定量构效关系模型合理化了调节与胆汁酸载体亲和力的空间和静电因素，其交叉验证、常规和预测的r2分别为0.63、0.96和0.69，表明该模型对载体亲和力具有良好的预测性。在24-27位定位一个电负性部分以及在侧链末端存在空间体积有利于结合。该模型表明在3、7、12和24位的取代可能会产生对载体具有合理亲和力的新底物。
