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

Abstract

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.

Peroxisome Proliferator-Activated Receptors as a Therapeutic Target in Asthma

“…All isoforms have approximately similar homology and consist of a DNA-binding domain at the N-terminus and a ligand-binding domain (LBD) at the C-terminus [34].…”

Synergistic protection against acute flurothyl‐induced seizures by adjuvant treatment of the ketogenic diet with the type 2 diabetes drug pioglitazone

“…In vivo treatment suggests that decanoic acid is a partial agonist as it improves glucose sensitivity and lipid profiles without weight gain in diabetic mice 47 . Other fatty acids and oxidized lipids (e.g., DHA) implicated in the classic KD have likewise been found to be PPARγ partial agonists 44,48 . Functionally, co-treatment with full and partial agonists may increase expression of gene sets important for seizure control.…”

“…One potentially important gene is the antioxidant catalase, which we and others have identified as upregulated by decanoic acid or the KD via PPARγ 46 (personal unpublished observations). Structurally, partial and full agonists bind to different sites within the PPARγ βινδινγ pocket 44,48 raising the possibility that cooperativity may occur between sites; thus, enhancing the transcriptional activity of PPARγ similar to the interactions of partial and full agonists on ligand gated receptors 49,50 . However, whether such an action occurs is unknown at this time.…”

“…38 Other fatty acids and oxidized lipids (e.g., docosahexaenoic acid) implicated in the classic KD have likewise been found to be PPARc partial agonists. 35,39 Functionally, cotreatment with full and partial agonists may increase expression of gene sets important for seizure control. One potentially important gene is the antioxidant catalase, which we and others have identified as upregulated by decanoic acid or the KD via PPARc 37 (personal unpublished observations).…”

Identification of potential drugs targeting L,L‐diaminopimelate aminotransferase of Chlamydia trachomatis: An integrative pharmacoinformatics approach

“…▵G SA is the difference in the surface area energies for the protein and the ligand. Because binding free energy score identifies plausible binding conformations among the docked complexes, the compounds passing this stringent ranking were used for further validation …”