Template CoMFA: The 3D-QSAR Grail?

Template CoMFA, a novel alignment methodology for training or test set structures in 3D-QSAR, is introduced. Its two most significant advantages are its complete automation and its ability to derive a single combined model from multiple structural series affecting a biological target. Its only two inputs are one or more “template” structures having 3D coordinates that share some Cartesian space, as may result from X-ray crystallography or pharmacophoric hypothesis, and one or more connectivity-only SAR tables associated with a common target. Template CoMFA also overcomes the major disadvantages of both existing 3D-QSAR alignment methodologies, specifically the tedium and subjectivity of familiar ad hoc approaches, and the awkwardness, occasional physicochemical heresies, and structural scope limitations of the purely topomer approach. The template CoMFA algorithms are described, and two of its application classes are presented. The first class, general models of binding to factor Xa and P38 map kinase, uses crystallographic structures as templates, with the encouraging result that the statistical qualities of each of these two combined models are equivalent to those of their constituent individual series models. The second, 15 data sets originally collected for validation of topomer CoMFA, with arbitrary structures as templates, confirms that the modeling power of template CoMFA resembles that of its predecessors.本文介绍了一种用于三维定量构效关系（3D-QSAR）训练集或测试集结构比对的新型比对方法——模板比较分子场分析法（Template CoMFA）。该方法最显著的两大优势在于其完全自动化的操作流程，以及能够从作用于同一生物靶点的多组结构序列中构建出单一整合模型的能力。其仅需两类输入数据：一类是具备三维坐标且共享部分笛卡尔空间的一个或多个“模板”结构，此类结构可通过X射线晶体衍射实验或药效团假说获得；另一类是与同一靶点相关联的一个或多个仅含连接关系的构效关系（SAR，Structure-Activity Relationship）表。模板CoMFA同时克服了现有两类3D-QSAR比对方法的主要缺陷：一是传统特设方法的繁琐操作与主观随意性，二是纯拓扑子场法存在的操作生硬、偶尔出现物理化学性质违背常理的问题，以及结构适用范围受限的不足。本文对模板CoMFA的算法原理进行了阐述，并展示了其两类应用场景。第一类应用场景是以晶体衍射结构作为模板，构建结合于凝血因子Xa与P38丝裂原活化蛋白激酶的通用模型，实验结果令人鼓舞：这两类整合模型的统计性能均与其各自独立结构序列所构建的模型相当。第二类应用场景则选取最初用于验证拓扑比较分子场分析法（topomer CoMFA）的15个数据集，并以任意结构作为模板，实验结果证实模板CoMFA的建模能力与其前代方法不相上下。