Paying the Price of Desolvation in Solvent-Exposed Protein Pockets: Impact of Distal Solubilizing Groups on Affinity and Binding Thermodynamics in a Series of Thermolysin Inhibitors
Paying the Price of Desolvation in Solvent-Exposed Protein Pockets: Impact of Distal Solubilizing Groups on Affinity and Binding Thermodynamics in a Series of Thermolysin Inhibitors
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DOI：
10.1021/acs.jmedchem.7b00490
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发表时间：
2017-07-13
影响因子：
7.3
通讯作者：
Klebe, Gerhard
中科院分区：
文献类型：
--
作者：
Cramer, Jonathan;Krimmer, Stefan G.;Klebe, Gerhard
在先导化合物优化中，开放的、暴露于溶剂的蛋白质口袋通常被忽视为潜在的结合位点。由于本体溶剂接近，研究人员倾向于在抑制剂支架上附着带电极性基团，以提高溶解度和药代动力学特性。很少有人认为蛋白质配体复合物的第一水合壳中水重组的溶剂效应会对结合产生显着影响。我们研究了嗜热菌蛋白酶抑制剂的热力学指纹，该抑制剂具有末端带电的铵基团，这些铵基团逐渐从远端、溶剂暴露的位置拉入平坦的碗形S-2'口袋中。即使对于最远的连接，蛋白质-溶剂界面附近的极性基团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。通过与疏水性类似物的直接比较，记录了显着的 180 倍亲和力损失，这对在平坦开放口袋中的取代基的暴露末端连接极性配体溶解基团的流行策略提出了质疑。
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-2' 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.