Electrostatic Complementarity as a Fast and Effective Tool to Optimize Binding and Selectivity of Protein-Ligand Complexes
Electrostatic Complementarity as a Fast and Effective Tool to Optimize Binding and Selectivity of Protein-Ligand Complexes
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DOI：
10.1021/acs.jmedchem.8b01925
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发表时间：
2019-03-28
影响因子：
7.3
通讯作者：
Mackey, Mark D.
中科院分区：
文献类型：
--
作者：
Bauer, Matthias R.;Mackey, Mark D.
小分子及其各自受体之间的静电相互作用是分子识别所必需的，也是结合自由能的关键因素。因此，评估蛋白质-配体复合物的静电匹配为了解配体结合的原因以及如何改变以改善结合提供了重要的见解。理想情况下，在蛋白质-配体相互作用界面上，配体和蛋白质的静电电位应该最大化它们的互补性，同时最小化脱溶惩罚。在这项工作中，我们提出了一个快速有效的工具来计算和可视化蛋白质-配体复合物的静电互补性（EC）。我们从文献数据中编制了展示静电驱动结构-活性关系（SAR）的基准集，包括激酶、蛋白-蛋白相互作用和GPCR靶点，并使用这些基准集来证明EC方法可以可视化、合理化和预测静电驱动配体亲和力的变化，并有助于预测化合物的选择性。本文提出的分析EC的方法是一种强大而通用的药物设计工具。
Electrostatic interactions between small molecules and their respective receptors are essential for molecular recognition and are also key contributors to the binding free energy. Assessing the electrostatic match of protein-ligand complexes therefore provides important insights into why ligands bind and what can be changed to improve binding. Ideally, the ligand and protein electrostatic potentials at the protein-ligand interaction interface should maximize their complementarity while minimizing desolvation penalties. In this work, we present a fast and efficient tool to calculate and visualize the electrostatic complementarity (EC) of protein-ligand complexes. We compiled benchmark sets demonstrating electrostatically driven structure-activity relationships (SAR) from literature data, including kinase, protein-protein interaction, and GPCR targets, and used these to demonstrate that the EC method can visualize, rationalize, and predict electrostatically driven ligand affinity changes and help to predict compound selectivity. The methodology presented here for the analysis of EC is a powerful and versatile tool for drug design.