Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Basel, Switzerland.
J Chem Inf Model. 2011 Aug 22;51(8):1867-81. doi: 10.1021/ci200150p. Epub 2011 Jul 18.
Water molecules mediating polar interactions in ligand-protein complexes can substantially contribute to binding affinity and specificity. To account for such water molecules in computer-aided drug design, we performed an extensive search in the Cambridge Structural Database (CSD) to identify the geometrical criteria defining interactions of water molecules with ligand and protein. In addition, with ab initio calculations the propensity of ligand hydration was evaluated. Based on this information, we developed an algorithm (AcquaAlta) to reproduce water molecules bridging polar interactions between ligand and protein moieties. This approach was validated with 20 crystal structures and yielded a match of 76% between experimental and calculated water positions. When water molecules establishing only weak interactions with the protein were neglected, the match could be improved to 88%. Supported by a pharmacophore-based alignment tool, the solvation algorithm was then applied to the docking of oligopeptides to the periplasmic oligopeptide binding protein A (OppA). Calculated waters based on the crystal poses matched an average of 66% of the experimental waters. With water molecules calculated based on the docked ligands, the average match with the experimental waters dropped to 53%.
水分子在配体-蛋白质复合物中介导极性相互作用，可显著影响结合亲和力和特异性。为了在计算机辅助药物设计中考虑这些水分子，我们在剑桥结构数据库（CSD）中进行了广泛搜索，以确定定义水分子与配体和蛋白质相互作用的几何标准。此外，我们还通过从头计算评估了配体水合的倾向。基于这些信息，我们开发了一种算法（AcquaAlta）来再现水分子桥接配体和蛋白质部分之间的极性相互作用。该方法用 20 个晶体结构进行了验证，实验和计算的水分子位置之间的匹配率为 76%。当忽略与蛋白质仅存在弱相互作用的水分子时，匹配率可以提高到 88%。该方法通过基于药效团的对齐工具得到支持，然后将该溶剂化算法应用于寡肽与周质寡肽结合蛋白 A（OppA）的对接。基于晶体构象计算的水分子平均与 66%的实验水分子匹配。根据对接配体计算的水分子与实验水分子的平均匹配率降至 53%。
