探究过氧化物酶体增殖物激活受体γ配体结合域（PPARγ-LBD）与多不饱和脂肪酸及其抗炎代谢产物之间的分子间相互作用，以推断最具潜力的结合部分。
Probing the intermolecular interactions of PPARγ-LBD with polyunsaturated fatty acids and their anti-inflammatory metabolites to infer most potential binding moieties.
作者信息
Muralikumar Shalini, Vetrivel Umashankar, Narayanasamy Angayarkanni, N Das Undurti
机构信息
Centre for Bioinformatics, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Vision Research Foundation, Sankara Nethralaya, Chennai, 600 006, Tamil Nadu, India.
Department of Biochemistry and Cell Biology, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Vision Research Foundation, Sankara Nethralaya, Chennai, 600 006, Tamil Nadu, India.
出版信息
Lipids Health Dis. 2017 Jan 21;16(1):17. doi: 10.1186/s12944-016-0404-3.
BACKGROUND
PPARγ is an isoform of peroxisome proliferator-activated receptor (PPAR) belonging to a super family of nuclear receptors. PPARγ receptor is found to play a crucial role in the modulation of lipid and glucose homeostasis. Its commotion has been reported to play a significant role in a broad spectrum of diseases such as type 2 diabetes mellitus, inflammatory diseases, Alzheimer's disease, and in some cancers. Hence, PPARγ is an important therapeutic target. Polyunsaturated fatty acids (PUFAs) and their metabolites (henceforth referred to as bioactive lipids) are known to function as agonists of PPARγ. However, agonistic binding modes and affinity of these ligands to PPARγ are yet to be deciphered.
METHODS
In this study, we performed a comparative molecular docking, binding free energy calculation and molecular dynamics simulation to infer and rank bioactive lipids based on the binding affinities with the ligand binding domain (LBD) of PPARγ.
RESULTS
The results inferred affinity in the order of resolvin E1 > neuroprotectin D1 > hydroxy-linoleic acid > docosahexaenoic acid > lipoxin A4 > gamma-linolenic acid, arachidonic acid > alpha-linolenic acid > eicosapentaenoic acid > linoleic acid. Of all the bioactive lipids studied, resolvin E1, neuroprotectin D1 and hydroxy-linoleic acid showed significant affinity comparable to proven PPARγ agonist namely, rosiglitazone, in terms of Glide XP docking score, H-bond formation with the key residues, binding free energy and stable complex formation with LBD favouring co-activator binding, as inferred through Molecular Dynamics trajectory analysis.
CONCLUSION
Hence, these three bioactive lipids (resolvin E1, neuroprotectin D1 and hydroxy-linoleic acid) may be favourably considered as ideal drug candidates in therapeutic modulation of clinical conditions such as type 2 DM, Alzheimer's disease and other instances where PPARγ is a key player.
背景
PPARγ是过氧化物酶体增殖物激活受体（PPAR）的一种亚型，属于核受体超家族。研究发现PPARγ受体在调节脂质和葡萄糖稳态中起关键作用。据报道，其紊乱在多种疾病中起重要作用，如2型糖尿病、炎症性疾病、阿尔茨海默病以及某些癌症。因此，PPARγ是一个重要的治疗靶点。多不饱和脂肪酸（PUFAs）及其代谢产物（以下简称生物活性脂质）已知可作为PPARγ的激动剂。然而，这些配体与PPARγ的激动性结合模式和亲和力尚未得到阐明。
方法
在本研究中，我们进行了比较分子对接、结合自由能计算和分子动力学模拟，以根据生物活性脂质与PPARγ配体结合域（LBD）的结合亲和力进行推断和排序。
结果
结果推断亲和力顺序为：消退素E1＞神经保护素D1＞羟基 - 亚油酸＞二十二碳六烯酸＞脂氧素A4＞γ - 亚麻酸、花生四烯酸＞α - 亚麻酸＞二十碳五烯酸＞亚油酸。在所有研究的生物活性脂质中，就Glide XP对接分数、与关键残基形成氢键、结合自由能以及通过分子动力学轨迹分析推断的与有利于共激活剂结合的LBD形成稳定复合物而言，消退素E1、神经保护素D1和羟基 - 亚油酸显示出与已证实的PPARγ激动剂罗格列酮相当的显著亲和力。
结论
因此，这三种生物活性脂质（消退素E1、神经保护素D1和羟基 - 亚油酸）在治疗调节2型糖尿病、阿尔茨海默病等临床病症以及其他PPARγ起关键作用的情况下，可被视为理想的候选药物。
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