Distinct binding hotspots for natural and synthetic agonists of FFA4 from in silico approaches.

IF 2.8 4区 医学 Q3 CHEMISTRY, MEDICINAL
Molecular Informatics Pub Date : 2024-10-01 Epub Date: 2024-07-24 DOI:10.1002/minf.202400046
Guillaume Patient, Corentin Bedart, Naim A Khan, Nicolas Renault, Amaury Farce
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引用次数: 0

Abstract

FFA4 has gained interest in recent years since its deorphanization in 2005 and the characterization of the Free Fatty Acids receptors family for their therapeutic potential in metabolic disorders. The expression of FFA4 (also known as GPR120) in numerous organs throughout the human body makes this receptor a highly potent target, particularly in fat sensing and diet preference. This offers an attractive approach to tackle obesity and related metabolic diseases. Recent cryo-EM structures of the receptor have provided valuable information for a potential active state although the previous studies of FFA4 presented diverging information. We performed molecular docking and molecular dynamics simulations of four agonist ligands, TUG-891, Linoleic acid, α-Linolenic acid, and Oleic acid, based on a homology model. Our simulations, which accumulated a total of 2 μs of simulation, highlighted two binding hotspots at Arg992.64 and Lys293 (ECL3). The results indicate that the residues are located in separate areas of the binding pocket and interact with various types of ligands, implying different potential active states of FFA4 and a highly adaptable binding intra-receptor pocket. This article proposes additional structural characteristics and mechanisms for agonist binding that complement the experimental structures.

从硅学方法看天然和合成 FFA4 激动剂的不同结合热点。
自 2005 年 FFA4 被非形态化,以及游离脂肪酸受体家族在新陈代谢疾病中的治疗潜力被定性以来,FFA4 近年来越来越受到人们的关注。FFA4(又称 GPR120)在人体众多器官中的表达使该受体成为一个非常有效的靶点,尤其是在脂肪感应和饮食偏好方面。这为解决肥胖和相关代谢疾病提供了一种极具吸引力的方法。尽管以前对 FFA4 的研究提供了不同的信息,但最近该受体的低温电子显微镜结构为潜在的活性状态提供了宝贵的信息。我们基于同源模型对四种激动剂配体 TUG-891、亚油酸、α-亚麻酸和油酸进行了分子对接和分子动力学模拟。我们的模拟总共耗时 2 μs,突出显示了 Arg992.64 和 Lys293(ECL3)处的两个结合热点。结果表明,这两个残基分别位于结合口袋的不同区域,并与不同类型的配体相互作用,这意味着 FFA4 具有不同的潜在活性状态和一个具有高度适应性的受体内结合口袋。本文提出了与实验结构互补的其他结构特征和激动剂结合机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular Informatics
Molecular Informatics CHEMISTRY, MEDICINAL-MATHEMATICAL & COMPUTATIONAL BIOLOGY
CiteScore
7.30
自引率
2.80%
发文量
70
审稿时长
3 months
期刊介绍: Molecular Informatics is a peer-reviewed, international forum for publication of high-quality, interdisciplinary research on all molecular aspects of bio/cheminformatics and computer-assisted molecular design. Molecular Informatics succeeded QSAR & Combinatorial Science in 2010. Molecular Informatics presents methodological innovations that will lead to a deeper understanding of ligand-receptor interactions, macromolecular complexes, molecular networks, design concepts and processes that demonstrate how ideas and design concepts lead to molecules with a desired structure or function, preferably including experimental validation. The journal''s scope includes but is not limited to the fields of drug discovery and chemical biology, protein and nucleic acid engineering and design, the design of nanomolecular structures, strategies for modeling of macromolecular assemblies, molecular networks and systems, pharmaco- and chemogenomics, computer-assisted screening strategies, as well as novel technologies for the de novo design of biologically active molecules. As a unique feature Molecular Informatics publishes so-called "Methods Corner" review-type articles which feature important technological concepts and advances within the scope of the journal.
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