Takeuchi Y, Shands E F, Beusen D D, Marshall G R
Center for Molecular Design and Department of Computer Science, Washington University, St. Louis, Missouri 63110-1012, USA.
J Med Chem. 1998 Sep 10;41(19):3609-23. doi: 10.1021/jm9700171.
Constrained systematic search was used in an exhaustive conformational analysis of a structurally diverse set of substance P (SP) antagonists to identify a unique hypothesis for their bound conformation at the neurokinin-1 receptor. In this conformation, two aromatic groups essential for high affinity adopt a perpendicular or edge-on arrangement. This pharmacophore hypothesis for the receptor-bound conformation was used in a comparative molecular field analysis (CoMFA) of an expanded set of SP antagonists, and the predictive ability of the resulting three-dimensional quantitative structure-activity relationship (3D-QSAR) was evaluated against a test set of SP antagonists different from those in the training set. This CoMFA model based on the Constrained Search alignment yielded significant cross-validated, conventional, and predictive r2 values equal to 0.70, 0.93, and 0.82, respectively. For comparison, the SP antagonists were forced into an alternative poorer alignment in which the two aromatic rings were parallel and then subjected to a CoMFA analysis. Both the parallel and perpendicular arrangements of the aromatic rings are seen in X-ray structures of SP antagonists and have been proposed as candidates for the receptor-bound conformation. The parallel (or stacked) conformation yielded a poorer correlation with a cross-validated r2 = 0.57, a conventional r2 = 0.90, and a predictive r2 = 0.78. Our results indicate that although both alignments could generate a reasonable CoMFA correlation, the stacked conformation is unlikely to be the receptor-bound conformation, as the covalent structure of the antagonists precludes a common geometry in which the aromatic rings are stacked.
在对一组结构多样的P物质（SP）拮抗剂进行详尽的构象分析时，采用了受限系统搜索法，以确定它们在神经激肽-1受体上的结合构象的独特假设。在这种构象中，对高亲和力至关重要的两个芳香基团呈垂直或边缘对齐排列。这个关于受体结合构象的药效团假设被用于对一组扩展的SP拮抗剂进行比较分子场分析（CoMFA），并针对一组与训练集中不同的SP拮抗剂测试集评估所得三维定量构效关系（3D-QSAR）的预测能力。基于受限搜索比对的这个CoMFA模型分别产生了显著的交叉验证r2值、常规r2值和预测r2值，分别为0.70、0.93和0.82。为作比较，将SP拮抗剂强制排成一种较差的替代比对，其中两个芳香环是平行的，然后进行CoMFA分析。芳香环的平行和垂直排列在SP拮抗剂的X射线结构中都可见，并且已被提议作为受体结合构象的候选结构。平行（或堆叠）构象产生的相关性较差，交叉验证r2 = 0.57，常规r2 = 0.90，预测r2 = 0.78。我们的结果表明，虽然两种比对都能产生合理的CoMFA相关性，但堆叠构象不太可能是受体结合构象，因为拮抗剂的共价结构排除了芳香环堆叠的常见几何形状。
