Pastor M, Cruciani G, Watson K A
Department of Pharmacology, University of Alcala, Alcala de Henares, Spain.
J Med Chem. 1997 Dec 5;40(25):4089-102. doi: 10.1021/jm970273d.
Water present in a ligand binding site of a protein has been recognized to play a major role in ligand-protein interactions. To date, rational drug design techniques do not usually incorporate the effect of these water molecules into the design strategy. This work represents a new strategy for including water molecules into a three-dimensional quantitative structure-activity relationship analysis using a set of glucose analogue inhibitors of glycogen phosphorylase (GP). In this series, the structures of the ligand-enzyme complexes have been solved by X-ray crystallography, and the positions of the ligands and the water molecules at the ligand binding site are known. For the structure-activity analysis, some water molecules adjacent to the ligands were included into an assembly which encompasses both the inhibitor and the water involved in the ligand-enzyme interaction. The mobility of some water molecules at the ligand binding site of GP gives rise to differences in the ligand-water assembly which have been accounted for using a simulation study involving force-field energy calculations. The assembly of ligand plus water was used in a GRID/GOLPE analysis, and the models obtained compare favorably with equivalent models when water was excluded. Both models were analyzed in detail and compared with the crystallographic structures of the ligand-enzyme complexes in order to evaluate their ability to reproduce the experimental observations. The results demonstrate that incorporation of water molecules into the analysis improves the predictive ability of the models and makes them easier to interpret. The information obtained from interpretation of the models is in good agreement with the conclusions derived from the structural analysis of the complexes and offers valuable insights into new characteristics of the ligands which may be exploited for the design of more potent inhibitors.
蛋白质配体结合位点中的水已被认为在配体 - 蛋白质相互作用中起主要作用。迄今为止，合理药物设计技术通常不会将这些水分子的影响纳入设计策略。这项工作提出了一种新策略，即将水分子纳入使用一组糖原磷酸化酶（GP）葡萄糖类似物抑制剂进行的三维定量构效关系分析中。在这个系列中，配体 - 酶复合物的结构已通过X射线晶体学解析，并且配体和配体结合位点处水分子的位置是已知的。对于构效分析，一些与配体相邻的水分子被纳入一个集合中，该集合既包括抑制剂又包括参与配体 - 酶相互作用的水。GP配体结合位点处一些水分子的流动性导致配体 - 水集合的差异，这已通过涉及力场能量计算的模拟研究进行了解释。配体加水的集合用于GRID/GOLPE分析，得到的模型与排除水时的等效模型相比具有优势。对这两个模型都进行了详细分析，并与配体 - 酶复合物的晶体结构进行比较，以评估它们重现实验观察结果的能力。结果表明，在分析中纳入水分子可提高模型的预测能力并使其更易于解释。从模型解释中获得的信息与从复合物结构分析得出的结论高度一致，并为配体的新特性提供了有价值的见解，这些见解可用于设计更有效的抑制剂。
