Absolute Binding Free Energy Calculation and Design of a Subnanomolar Inhibitor of Phosphodiesterase-10

Zhe Li; Yiyou Huang; Yinuo Wu; Jingyi Chen; Deyan Wu; Chang Guo Zhan; Hai Bin Luo

doi:10.1021/acs.jmedchem.8b01763

Absolute Binding Free Energy Calculation and Design of a Subnanomolar Inhibitor of Phosphodiesterase-10

Zhe Li
, Yiyou Huang
, Yinuo Wu
, Jingyi Chen
, Deyan Wu
, Chang Guo Zhan
, Hai Bin Luo

Pharmaceutical Sciences

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

57 Scopus citations

Abstract

Accurate prediction of absolute protein-ligand binding free energy could considerably enhance the success rate of structure-based drug design but is extremely challenging and time-consuming. Free energy perturbation (FEP) has been proven reliable but is limited to prediction of relative binding free energies of similar ligands (with only minor structural differences) in binding with a same drug target in practical drug design applications. Herein, a Gaussian algorithm-enhanced FEP (GA-FEP) protocol has been developed to enhance the FEP simulation performance, enabling to efficiently carry out the FEP simulations on vanishing the whole ligand and, thus, predict the absolute binding free energies (ABFEs). Using the GA-FEP protocol, the FEP simulations for the ABFE calculation (denoted as GA-FEP/ABFE) can achieve a satisfactory accuracy for both structurally similar and diverse ligands in a dataset of more than 100 receptor-ligand systems. Further, our GA-FEP/ABFE-guided lead optimization against phosphodiesterase-10 led to the discovery of a subnanomolar inhibitor (IC ₅₀ = 0.87 nM, ~2000-fold improvement in potency) with cocrystal confirmation.

Original language	English
Pages (from-to)	2099-2111
Number of pages	13
Journal	Journal of Medicinal Chemistry
Volume	62
Issue number	4
DOIs	https://doi.org/10.1021/acs.jmedchem.8b01763
State	Published - Feb 28 2019

Bibliographical note

Publisher Copyright:
© 2019 American Chemical Society.

Funding

This work was supported by the National Key R&D Program of China (2017YFB0202600), Natural Science Foundation of China (21572279, 21877134, 81522041, and 21402243), Science Foundation of Guangdong Province (2018A030313215 and 2014A020210009), Fundamental Research Funds for the Central Universities (Sun Yat-Sen University, 17ykjc03 and 18ykpy23), Guangdong Province Higher Vocational Colleges & Schools Pearl River Scholar Funded Scheme (2016), and the National Science Foundation (NSF, grant CHE-1111761). We cordially thank Prof. H. Ke from the Department of Biochemistry and Biophysics at the University of North Carolina, Chapel Hill, for his help with PDEs.

Funders	Funder number
Department of Biochemistry and Biophysics at the University of North Carolina
National Key Basic Research Program of China	2017YFB0202600
National Science Foundation Arctic Social Science Program	CHE-1111761
National Science Foundation Arctic Social Science Program
National Natural Science Foundation of China (NSFC)	21877134, 21572279, 81522041, 21402243
National Natural Science Foundation of China (NSFC)
Sun Yat-Sen University	17ykjc03, 18ykpy23
Sun Yat-Sen University
Natural Science Foundation of Guangdong Province	2014A020210009, 2018A030313215
Natural Science Foundation of Guangdong Province
Fundamental Research Funds for the Central Universities
Guangdong Province Higher Vocational Colleges and Schools Pearl River Scholar Funded Scheme

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.8b01763

Cite this

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title = "Absolute Binding Free Energy Calculation and Design of a Subnanomolar Inhibitor of Phosphodiesterase-10",

abstract = " Accurate prediction of absolute protein-ligand binding free energy could considerably enhance the success rate of structure-based drug design but is extremely challenging and time-consuming. Free energy perturbation (FEP) has been proven reliable but is limited to prediction of relative binding free energies of similar ligands (with only minor structural differences) in binding with a same drug target in practical drug design applications. Herein, a Gaussian algorithm-enhanced FEP (GA-FEP) protocol has been developed to enhance the FEP simulation performance, enabling to efficiently carry out the FEP simulations on vanishing the whole ligand and, thus, predict the absolute binding free energies (ABFEs). Using the GA-FEP protocol, the FEP simulations for the ABFE calculation (denoted as GA-FEP/ABFE) can achieve a satisfactory accuracy for both structurally similar and diverse ligands in a dataset of more than 100 receptor-ligand systems. Further, our GA-FEP/ABFE-guided lead optimization against phosphodiesterase-10 led to the discovery of a subnanomolar inhibitor (IC 50 = 0.87 nM, \textasciitilde{}2000-fold improvement in potency) with cocrystal confirmation.",

author = "Zhe Li and Yiyou Huang and Yinuo Wu and Jingyi Chen and Deyan Wu and Zhan, \{Chang Guo\} and Luo, \{Hai Bin\}",

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AU - Wu, Deyan

AU - Zhan, Chang Guo

AU - Luo, Hai Bin

PY - 2019/2/28

Y1 - 2019/2/28

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Absolute Binding Free Energy Calculation and Design of a Subnanomolar Inhibitor of Phosphodiesterase-10

Abstract

Bibliographical note

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ASJC Scopus subject areas

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