Institute of Pharmaceutical Chemistry, University of Marburg , Marbacher Weg 6, 35032 Marburg, Germany.
J Med Chem. 2017 Jul 13;60(13):5791-5799. doi: 10.1021/acs.jmedchem.7b00490. Epub 2017 Jun 22.
In lead optimization, open, solvent-exposed protein pockets are often disregarded as prospective binding sites. Because of bulk-solvent proximity, researchers are instead enticed to attach charged polar groups at inhibitor scaffolds to improve solubility and pharmacokinetic properties. It is rarely considered that solvent effects from water reorganization in the first hydration shell of protein-ligand complexes can have a significant impact on binding. We investigate the thermodynamic fingerprint of thermolysin inhibitors featuring terminal charged ammonium groups that are gradually pulled from a distal, solvent-exposed position into the flat, bowl-shaped S' pocket. Even for the most remote attachment, costs for partial desolvation of the polar group next to the protein-solvent interface are difficult to compensate by interactions with the protein or surrounding water molecules. Through direct comparison with hydrophobic analogues, a significant 180-fold affinity loss was recorded, which questions popular strategies to attach polar ligand-solubilizing groups at the exposed terminus of substituents accommodated in flat open pockets.
在先导化合物优化中，通常会忽略暴露在溶剂中的蛋白质口袋作为潜在的结合位点。由于溶剂的临近，研究人员更倾向于在抑制剂骨架上连接带电的极性基团，以提高其溶解度和药代动力学性质。很少有人考虑到，来自蛋白质-配体复合物第一层水合壳的溶剂重排对结合的影响可能非常显著。我们研究了末端带有带电荷的铵基团的糜蛋白酶抑制剂的热力学特征，这些铵基团逐渐从远端的溶剂暴露位置被拉到平坦的 S' 口袋中。即使是最远端的连接，极性基团与蛋白质-溶剂界面相邻部分的部分去溶剂化的成本也很难通过与蛋白质或周围水分子的相互作用来补偿。通过与疏水类似物的直接比较，记录到了显著的 180 倍亲和力损失，这对将极性配体增溶基团附着在容纳在平坦开放口袋中的取代基的暴露末端的流行策略提出了质疑。
