title: Probing the intermolecular interactions of PPARγ-LBD with polyunsaturated fatty acids and their anti-inflammatory metabolites to infer most potential binding moieties.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Centre for Bioinformatics, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Vision Research Foundation, Sankara Nethralaya, Chennai, 600 006, Tamil Nadu, India.
authors.forename: Shalini
authors.initials: S
authors.lastname: Muralikumar
authors.affiliation: Centre for Bioinformatics, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Vision Research Foundation, Sankara Nethralaya, Chennai, 600 006, Tamil Nadu, India. vumashankar@gmail.com.
authors.forename: Umashankar
authors.initials: U
authors.lastname: Vetrivel
authors.affiliation: 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.
authors.forename: Angayarkanni
authors.initials: A
authors.lastname: Narayanasamy
authors.affiliation: UND Life Sciences, 2020 S 360th St, # K202, Federal Way, WA, 98003, USA. Undurti@hotmail.com.|BioScience Research Centre, GVP College of Engineering, Visakhapatnam, 530048, India. Undurti@hotmail.com.
authors.forename: Undurti
authors.initials: U
authors.lastname: N Das
mesh_terms: D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000378:metabolism; D016718:Arachidonic Acid / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D004281:Docosahexaenoic Acids / Q000737:chemistry* / Q000378:metabolism; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D019787:Linoleic Acid / Q000737:chemistry / Q000378:metabolism; D008041:Linoleic Acids / Q000737:chemistry* / Q000378:metabolism; D044045:Lipoxins / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D047495:PPAR gamma / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D000077154:Rosiglitazone; D013816:Thermodynamics; D045162:Thiazolidinediones / Q000737:chemistry / Q000378:metabolism; D017962:alpha-Linolenic Acid / Q000737:chemistry / Q000378:metabolism; D017965:gamma-Linolenic Acid / Q000737:chemistry / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D008041:Linoleic Acids; D044045:Lipoxins; D047495:PPAR gamma; D045162:Thiazolidinediones; C040527:lipoxin A4; C487679:protectin D1; D000077154:Rosiglitazone; D017962:alpha-Linolenic Acid; C075806:8-hydroxylinoleic acid; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D017965:gamma-Linolenic Acid; D019787:Linoleic Acid; D015118:Eicosapentaenoic Acid; C499823:5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid
keywords: Bioactive lipids; Docking; Helix12; PPARγ; PUFA