Burke B J, Dunn W J, Hopfinger A J
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago 60612-7231.
J Med Chem. 1994 Oct 28;37(22):3775-88. doi: 10.1021/jm00048a014.
A generalized three-dimensional (3D) quantitative structure-property relationship (QSPR) formalism, based upon molecular shape analysis (MSA), has been applied to an analog series of pyridobenzodiazepinone inhibitors of muscarinic 2 (M2) and 3 (M3) receptors. The fundamental goal of this application is to establish MSA-3D-QSARs (P = A = inhibition activity) that are based upon identifying the active conformations of these flexible analogs. The repetitive use of partial least squares (PLS) analysis permits the construction of the MSA-3D-QSARs. In addition to molecular shape, the identification of the properties of a lipophilic binding site and specific nonallowed steric receptor sites govern the MSA-3D-QSARs. The M2 and M3 QSARs suggest receptor subtype specificity might be realized by targeting upon a specific nonallowed steric receptor site. One conformation, common to both M2 and M3 receptors, emerges as dominant in the optimum MSA-3D-QSARs. However, other similar conformations are also found to yield meaningful MSA-3D-QSARs.
一种基于分子形状分析（MSA）的广义三维（3D）定量结构-性质关系（QSPR）形式体系，已应用于毒蕈碱2（M2）和3（M3）受体的吡啶并苯二氮杂䓬酮抑制剂类似物系列。该应用的基本目标是建立基于识别这些柔性类似物活性构象的MSA-3D-QSARs（P = A =抑制活性）。偏最小二乘法（PLS）分析的重复使用允许构建MSA-3D-QSARs。除了分子形状外，亲脂性结合位点和特定非允许空间受体位点的性质识别也决定了MSA-3D-QSARs。M2和M3的QSARs表明，通过靶向特定的非允许空间受体位点可能实现受体亚型特异性。在最佳的MSA-3D-QSARs中，一种M2和M3受体共有的构象成为主导。然而，也发现其他类似构象能产生有意义的MSA-3D-QSARs。
