Probing the intermolecular interactions of PPARγ-LBD with polyunsaturated fatty acids and their anti-inflammatory metabolites to infer most potential binding moieties

Lipids in Health and Disease

Research

Umashankar Vetrivel¹  Shalini Muralikumar¹  Angayarkanni Narayanasamy²  Undurti N. Das³ 

[1] Centre for Bioinformatics, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Vision Research Foundation, Sankara Nethralaya, 600 006, Chennai, Tamil Nadu, India;Department of Biochemistry and Cell Biology, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Vision Research Foundation, Sankara Nethralaya, 600 006, Chennai, Tamil Nadu, India;UND Life Sciences, 2020 S 360th St, # K202, 98003, Federal Way, WA, USA;BioScience Research Centre, GVP College of Engineering, 530048, Visakhapatnam, India;

关键词: PPARγ;    PUFA;    Bioactive lipids;    Docking;    Helix12;   

DOI  :  10.1186/s12944-016-0404-3

 received in 2016-12-07, accepted in 2016-12-28,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundPPARγ 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.MethodsIn 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.ResultsThe 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.ConclusionHence, 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.

【 授权许可】

CC BY   
© The Author(s). 2017