Rational Design of Thermodynamic and Kinetic Binding Profiles by Optimizing Surface Water Networks Coating Protein-Bound Ligands
Rational Design of Thermodynamic and Kinetic Binding Profiles by Optimizing Surface Water Networks Coating Protein-Bound Ligands
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DOI：
10.1021/acs.jmedchem.6b00998
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发表时间：
2016-12-08
影响因子：
7.3
通讯作者：
Klebe, Gerhard
中科院分区：
文献类型：
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作者：
Krimmer, Stefan G.;Cramer, Jonathan;Klebe, Gerhard
先前研究的解决具有不同疏水取代基的溶剂可接近的S-2'口袋的嗜热菌蛋白酶抑制剂的同类系列显示了涂覆蛋白质结合的抑制剂的表面水层的调制。增加水分子的稳定性导致在实验上更有利的结合特征，总体上增强亲和力。基于这一观察，我们通过设计定制的P-2'取代基来优化该系列，以改善并进一步稳定地表水网络。应用分子动力学模拟来预测结合配体周围的假定水模式。随后，抑制剂的合成和高分辨率晶体学，微量热法和表面等离子体共振的特点。所设计的抑制剂之一建立了迄今为止测试的所有抑制剂中最明显的水网络，由几个融合的水多边形组成，并且相对于原始甲基化的母体配体显示出50倍的亲和力增强。值得注意的是，与其他测试的抑制剂相比，形成最完美的水网络的抑制剂还显示出显著延长的停留时间。
A previously studied congeneric series of thermolysin inhibitors addressing the solvent-accessible S-2' pocket with different hydrophobic substituents showed modulations of the surface water layers coating the protein-bound inhibitors. Increasing stabilization of water molecules resulted in an enthalpically more favorable binding signature, overall enhancing affinity. Based on this observation, we optimized the series by designing tailored P-2' substituents to improve and further stabilize the surface water network. MD simulations were applied to predict the putative water pattern around the bound ligands. Subsequently, the inhibitors were synthesized and characterized by high-resolution crystallography, microcalorimetry, and surface plasmon resonance. One of the designed inhibitors established the most pronounced water network of all inhibitors tested so far, composed of several fused water polygons, and showed 50-fold affinity enhancement with respect to the original methylated parent ligand. Notably, the inhibitor forming the most perfect water network also showed significantly prolonged residence time compared to the other tested inhibitors.