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

Zhaoxi Sun; Xiaohui Wang; John Z.H. Zhang

doi:10.1016/j.cplett.2019.03.020

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

Zhaoxi Sun, Xiaohui Wang, John Z.H. Zhang

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English (US)
Pages (from-to)	1-10
Number of pages	10
Journal	Chemical Physics Letters
Volume	723
DOIs	https://doi.org/10.1016/j.cplett.2019.03.020
State	Published - May 16 2019

ASJC Scopus subject areas

Physics and Astronomy(all)
Physical and Theoretical Chemistry

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

abstract = "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.",

author = "Zhaoxi Sun and Xiaohui Wang and Zhang, {John Z.H.}",

note = "Funding Information: This work was supported China Scholarship Council and National Key R&D Program of China (Grant no. 2016YFA0501700). Computer access to the CLAIX cluster of RWTH Aachen University and clusters of Forschungszentrum Juelich is gratefully acknowledged. We thank anonymous reviewers for valuable comments and critical reading. ",

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AU - Sun, Zhaoxi

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N1 - Funding Information: This work was supported China Scholarship Council and National Key R&D Program of China (Grant no. 2016YFA0501700). Computer access to the CLAIX cluster of RWTH Aachen University and clusters of Forschungszentrum Juelich is gratefully acknowledged. We thank anonymous reviewers for valuable comments and critical reading.

PY - 2019/5/16

Y1 - 2019/5/16

N2 - 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.

AB - 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.

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