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.

本文提出了一种用于三维定量构效关系（3D-QSAR）中训练集或测试集结构比对的新型方法：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特性，以及能够从作用于同一生物靶点的多组结构系列中构建单一整合模型的能力。该方法仅需两类输入数据：其一为一个或多个具备三维坐标且共享部分笛卡尔空间的“模板”结构，此类结构可通过X射线晶体衍射或药效团假说获得；其二为一个或多个与同一生物靶点相关的仅包含连接性信息的构效关系（SAR）表格。模板比较分子场分析法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性与主观性，二是纯拓扑子方法的操作不便、偶尔出现的物理化学悖谬以及结构适用范围受限的问题。本文详述了模板比较分子场分析法的算法原理，并展示了两类应用场景。第一类场景以凝血因子Xa与P38丝裂原活化蛋白激酶（P38 MAP激酶）的结合通用模型为例，采用晶体衍射结构作为模板，所得结果令人鼓舞：两类整合模型的统计性能均与其各自独立结构系列构建的模型相当。第二类场景则选取最初用于验证拓扑子比较分子场分析法（topomer CoMFA）的15个数据集，以任意结构作为模板，实验结果证实模板比较分子场分析法的建模性能与其前代方法相当。