Determination of binding affinities of 3-Hydroxy-3-Methylglutaryl Coenzyme A reductase inhibitors from free energy calculation

被引：10
作者：
Sun, Zhaoxi [1 ,2 ]
Wang, Xiaohui [1 ,3 ]
Zhang, John Z. H. [1 ,4 ,5 ]
机构：
[1] East China Normal Univ, Sch Chem & Mol Engn, State Key Lab Precis Spect, Shanghai 200062, Peoples R China
[2] Forschungszentrum Julich, Computat Biomed IAS 5 INM 9, D-52425 Julich, Germany
[3] USI, Inst Computat Sci, Via Giuseppe Buffi 13, CH-6900 Lugano, Ticino, Switzerland
[4] NYU Shanghai, NYU ECNU Ctr Computat Chem, Shanghai 200062, Peoples R China
[5] NYU, Dept Chem, New York, NY 10003 USA
来源：
CHEMICAL PHYSICS LETTERS | 2019年 / 723卷
基金：
国家重点研发计划;
关键词：
HMG-COA REDUCTASE; ENTROPY-ENTHALPY COMPENSATION; ADAPTIVE SAMPLING REGIME; VARIANCE MINIMIZATION; MM-PBSA; PROTEIN; SOLVATION; CRYSTAL; DESIGN;
D O I：
10.1016/j.cplett.2019.03.020
中图分类号：
O64 [物理化学（理论化学）、化学物理学];
学科分类号：
070304 ; 081704 ;
摘要：
Designed inhibitors of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase from previous experiments show high binding affinities. In this work, the binding affinities of these designed inhibitors are determined via free energy simulations. The calculated values agree well with the corresponding experimental results. Several structurally different inhibitors share extremely similar binding affinities. Detailed interaction analysis including the hydrogen bond profiles and the interaction energies between the ligand and its surroundings shows large enthalpy changes upon mutation from one ligand to another, while the binding affinities remain unchanged. This finding indicates the existence of entropy-enthalpy compensation.
引用
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页码：1 / 10
页数：10
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