Albany College of Pharmacy and Health Sciences , Vermont Campus, Colchester, Vermont 05446, United States.
J Chem Inf Model. 2011 May 23;51(5):1132-50. doi: 10.1021/ci200055s. Epub 2011 Apr 8.
For a rigorous analysis of the receptor-ligand binding, speciation of the ligands caused by ionization, tautomerism, covalent hydration, and dynamic stereoisomerism needs to be considered. Each species may bind in several orientations or conformations (modes), especially for flexible ligands and receptors. A thermodynamic description of the multispecies (MS), multimode (MM) binding events shows that the overall association constant is equal to the weighted sum of the sums of microscopic association constants of individual modes for each species, with the weights given by the unbound fractions of individual species. This expression is a prerequisite for a precise quantitative characterization of the ligand-receptor interactions in both structure-based and ligand-based structure-activity analyses. We have implemented the MS-MM correlation expression into the comparative molecular field analysis (CoMFA), which deduces a map of the binding site from structures and binding affinities of a ligand set, in the absence of experimental structural information on the receptor. The MS-MM CoMFA approach was applied to published data for binding to transthyretin of 28 thyroxine analogs, each forming up to four ionization species under physiological conditions. The published X-ray structures of several analogs, exhibiting multiple binding modes, served as templates for the MS-MM superposition of thyroxine analogs. Additional modes were generated for compounds with flexible alkyl substituents, to identify bound conformations. The results demonstrate that the MS-MM modification improved predictive abilities of the CoMFA models, even for the standard procedure with MS-MM selected species and modes. The predicted prevalences of individual modes and the generated receptor site model are in reasonable agreement with the available X-ray data. The calibrated model can help in the design of inhibitors of transthyretin amyloid fibril formation.
为了对受体-配体结合进行严格的分析，需要考虑配体由于电离、互变异构、共价水合和动态立体异构而引起的物种形成。每种物质都可能以几种取向或构象（模式）结合，尤其是对于灵活的配体和受体。多物种（MS）、多模式（MM）结合事件的热力学描述表明，总体结合常数等于各个模式下各个物种的微观结合常数之和的加权和，权重由各个物种的未结合分数给出。该表达式是对基于结构和基于配体的结构活性分析中配体-受体相互作用进行精确定量描述的前提。我们已经将 MS-MM 相关表达式实现到比较分子场分析（CoMFA）中，该分析从配体集的结构和结合亲和力推导出结合位点图，而无需受体的实验结构信息。MS-MM CoMFA 方法应用于结合转甲状腺素蛋白的 28 种甲状腺素类似物的发表数据，在生理条件下，每种类似物形成多达四个电离物质。几个类似物的发表 X 射线结构，表现出多种结合模式，作为甲状腺素类似物的 MS-MM 叠加模板。对于具有灵活烷基取代基的化合物，生成了附加模式，以确定结合构象。结果表明，即使对于具有 MS-MM 选择物种和模式的标准程序，MS-MM 修饰也提高了 CoMFA 模型的预测能力。个别模式的预测优势和生成的受体位点模型与可用的 X 射线数据基本一致。校准后的模型可以帮助设计转甲状腺素蛋白淀粉样纤维形成的抑制剂。
