Doddareddy Munikumar Reddy, Jung Hee Kyung, Cha Joo Hwan, Cho Yong Seo, Koh Hun Yeong, Chang Moon Ho, Pae Ae Nim
Biochemicals Research Center, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, South Korea.
Bioorg Med Chem. 2004 Apr 1;12(7):1613-21. doi: 10.1016/j.bmc.2004.01.028.
Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of isoxazolyl compounds as a potent T-type calcium channel blockers. A set of 24 structurally similar compounds served to establish the model. Four different conformations of the most active compound were used as template structures for the alignment, three of which were obtained from Catalyst pharmacophore modeling and one by using SYBYL random search option. All CoMFA and CoMSIA models gave cross-validated r(2) (q(2)) value of more than 0.5 and conventional r(2) value of more than 0.85. The predictive ability of the models was validated by an external test set of 10 compounds, which gave satisfactory pred r(2) values ranging from 0.577 to 0.866 for all models. Best predictions were obtained with CoMFA std model of Conformer no: 3 alignment (q(2)=0.756, r(2)=0.963), giving predictive r(2) value of 0.866 for the test set. CoMFA and CoMSIA contour maps were used to analyze the structural features of the ligands accounting for the activity in terms of positively contributing physicochemical properties: steric, electrostatic, hydrophobic and hydrogen bonding fields.
对一系列作为强效T型钙通道阻滞剂的异恶唑基化合物进行了比较分子场分析（CoMFA）和比较分子相似性指数分析（CoMSIA）。一组24种结构相似的化合物用于建立模型。最具活性的化合物的四种不同构象用作比对的模板结构，其中三种通过Catalyst药效团建模获得，一种通过使用SYBYL随机搜索选项获得。所有CoMFA和CoMSIA模型的交叉验证r(2)（q(2)）值均大于0.5，常规r(2)值大于0.85。通过10种化合物的外部测试集验证了模型的预测能力，所有模型的预测r(2)值在0.577至0.866之间，结果令人满意。使用构象异构体编号为3的比对的CoMFA标准模型获得了最佳预测结果（q(2)=0.756，r(2)=0.963），测试集的预测r(2)值为0.866。CoMFA和CoMSIA等高线图用于根据对活性有正向贡献的物理化学性质（空间、静电、疏水和氢键场）分析配体的结构特征。
