TCM Group, Cavendish Laboratory , University of Cambridge , 19 J J Thomson Avenue , Cambridge CB3 0HE , U.K.
Tri-Institutional Therapeutics Discovery Institute , Belfer Research Building, 413 East 69th Street, 16th Floor, Box 300 , New York 10021 , United States.
J Chem Theory Comput. 2019 Nov 12;15(11):6504-6512. doi: 10.1021/acs.jctc.9b00976. Epub 2019 Oct 23.
We present an explicit solvent alchemical free-energy method for optimizing the partial charges of a ligand to maximize the binding affinity with a receptor. This methodology can be applied to known ligand-protein complexes to determine an optimized set of ligand partial atomic changes. Three protein-ligand complexes have been optimized in this work: FXa, P38, and the androgen receptor. The sets of optimized charges can be used to identify design principles for chemical changes to the ligands which improve the binding affinity for all three systems. In this work, beneficial chemical mutations are generated from these principles and the resulting molecules tested using free-energy perturbation calculations. We show that three quarters of our chemical changes are predicted to improve the binding affinity, with an average improvement for the beneficial mutations of approximately 1 kcal/mol. In the cases where experimental data are available, the agreement between prediction and experiment is also good. The results demonstrate that charge optimization in explicit solvent is a useful tool for predicting beneficial chemical changes such as pyridinations, fluorinations, and oxygen to sulfur mutations.
我们提出了一种显溶剂化学计量自由能方法，用于优化配体的部分电荷，以最大化其与受体的结合亲和力。该方法可应用于已知的配体-蛋白质复合物，以确定配体部分原子变化的最佳集合。在这项工作中，优化了三种蛋白质-配体复合物：FXa、P38 和雄激素受体。可以使用这些优化的电荷集来确定可改善所有三种系统结合亲和力的配体化学变化的设计原则。在这项工作中，从这些原则中生成有益的化学突变，并用自由能扰动计算测试所得分子。我们表明，我们的化学变化中有四分之三预计会提高结合亲和力，有益突变的平均改善约为 1 kcal/mol。在有实验数据的情况下，预测与实验之间的一致性也很好。结果表明，显溶剂中的电荷优化是预测有益化学变化（如吡啶化、氟化和氧到硫突变）的有用工具。
