Structural requirement of RARγ agonism through computational aspects

Haihan Liu; Baichun Hu; Jiasi Luan; Yuqing Sun; Shizun Wang; Weixai Li; Lu Chen; Hanxun Wang; Yinli Gao; Jian Wang

doi:10.1007/s00894-023-05507-6

Structural requirement of RARγ agonism through computational aspects

J Mol Model. 2023 Mar 24;29(4):108. doi: 10.1007/s00894-023-05507-6.

Authors

Haihan Liu^{1

2

3}, Baichun Hu^{1

2

3}, Jiasi Luan^{1

2

4}, Yuqing Sun^{1

2

3}, Shizun Wang^{1

2

3}, Weixai Li^{1

2

3}, Lu Chen^{1

2

3}, Hanxun Wang^{1

2

3}, Yinli Gao^{1

2

3}, Jian Wang^{5

6

7}

Affiliations

¹ Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.
² Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang, 110016, China.
³ School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.
⁴ School of Medical Devices, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.
⁵ Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China. jianwang@syphu.edu.cn.
⁶ Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang, 110016, China. jianwang@syphu.edu.cn.
⁷ School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China. jianwang@syphu.edu.cn.

PMID: 36964229
DOI: 10.1007/s00894-023-05507-6

Abstract

Context: RARγ is a therapeutic target for many skin diseases and has potential in cancer treatment. In the current study, we put forward a comprehensive structure-activity relationship study of third and fourth generations of RARγ agonists, addressing multiple crystal structures of RARγ complexes and approved drugs. Adapalene and Trifarotene, through hybrid strategies including protein contacts Atlas analysis, molecular docking, dynamics simulations, MM-GBSA, ASM, and pharmacophore modeling. Our result revealed crucial amino acids Arg267, Ser278, Phe288, Phe230, Met272, Leu271, and Leu268 within the RARγ pocket, as well as pharmacophore features such as two hydrophobic groups, two aromatic rings, and negative ionic features, which are essential for the binding of RARγ agonists. Based on this study, the binding mechanism of RARγ agonists was elucidated, which will be helpful for the rational design of new RARγ agonists for skin diseases and cancer treatment.

Methods: In this study, Schrödinger suite 2021-2 with OPLS_4 force field, Discovery Studio program 3.0, LigandScout 4.3, and PyMOL are utilized in the investigation.

Keywords: Alanine scanning mutagenesis; Binding free energy calculation; Molecular dynamics simulations; Pharmacophore modeling; RARγ agonists.

MeSH terms

Molecular Docking Simulation
Molecular Dynamics Simulation*
Quantitative Structure-Activity Relationship*

Abstract

MeSH terms

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