Agonism activities of lyso-phosphatidylcholines (LPC) Ligands binding to peroxisome proliferator-activated receptor gamma (PPARγ) (original) (raw)
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International Journal of Molecular Sciences, 2015
The structural and dynamical properties of the peroxisome proliferator-activated receptor γ (PPARγ) nuclear receptor have been broadly studied in its agonist state but little is known about the key features required for the receptor antagonistic activity. Here we report a series of molecular dynamics (MD) simulations in combination with free energy estimation of the recently discovered class of non-covalent PPARγ antagonists. Their binding modes and dynamical behavior are described in details. Two key interactions have been detected within the cavity between helices H3, H11 and the activation helix H12, as well as with H12. The strength of the ligand-amino acid residues interactions has been analyzed in relation to the specificity of the ligand dynamical and antagonistic features. According to our results, the PPARγ activation helix does not undergo dramatic conformational changes, as seen in other nuclear receptors, but rather perturbations that occur through a significant ligand-induced reshaping of the ligand-receptor and the receptor-coactivator binding pockets. The H12 residue Tyr473 and the charge clamp residue Glu471 play a central role for the receptor transformations. Our results also demonstrate that MD can be a helpful tool for the compound phenotype characterization (full agonists, partial agonists or antagonists) when insufficient experimental data are available.
Current computer-aided drug design, 2017
Metabolic syndrome is a matrix of different metabolic disorders which are the leading cause of death in human beings. Peroxysome proliferated activated receptor (PPAR) is a nuclear receptor involvedin metabolism of fats and glucose. In order to explore structural requirements for selective PPAR modulators to control lipid and carbohydrate metabolism, the multi-cheminformatics studies have been performed. Insilico modeling studies have been performed on a diverse set of PPAR modulators through quantitative structural-activity relationship (QSAR), pharmacophore mapping and docking studies. It is observed that the presence of an amide fragment (-CONHRPh) has a detrimental effect while an aliphatic ether linkage has a beneficial effect on PPARα modulation. On the other hand, the presence of an amide fragment has a positive effect on PPARδ modulation, but the aliphatic ether linkage and substituted aromatic ring in the molecular scaffold are very much essential for imparting potent and s...
We report both automated rigid and flexible ligand docking simulations performed on fifty peroxisome proliferator-activated receptor (PPAR-c) agonists, namely, glitazones. The binding conformations and binding affinities of these agonists were obtained by the use of the Autodock 4.1 with Lamarckian genetic algorithm (LGA). All the 50 flexible docks are considered as well-docked as all of them were bound to the ligand binding domain of PPAR-c. The predicted binding affinity values (pKa) were found to have some degree of correlation with their experimental in vivo activity values. The head group hydrogen bond interactions via H323 and H449 histidine residues were found to play a significant role. The results obtained will be valuable in designing newer selective PPAR-c agonists.
Structural and Dynamic Elucidation of a Non-acid PPARγ Partial Agonist: SR1988
Nuclear Receptor Research, 2018
Targeting peroxisome proliferator-activated receptor γ (PPARγ) by synthetic compounds has been shown to elicit insulin sensitising properties in type 2 diabetics. Treatment with a class of these compounds, the thiazolidinediones (TZDs), has shown adverse side effects such as weight gain, fluid retention, and congestive heart failure. This is due to their full agonist properties on the receptor, where a number of genes are upregulated beyond normal physiological levels. Lessened transactivation of PPARγ by partial agonists has proved beneficial in terms of reducing side effects, while still maintaining insulin sensitising properties. However, some partial agonists have been associated with unfavourable pharmacokinetic profiles due to their acidic moieties, often causing partitioning to the liver. Here we present SR1988, a new partial agonist with favourable non-acid chemical properties. We used a combination of X-ray crystallography and hydrogen/deuterium exchange (HDX) to elucidate the structural basis for reduced activation of PPARγ by SR1988. This structural analysis reveals a mechanism that decreases stabilisation of the AF2 coactivator binding surface by the ligand.
Journal of Medicinal Chemistry, 2006
Peroxisome proliferator-activated receptor γ (PPARγ) is well-known as the receptor of thiazolidinedione antidiabetic drugs. In this paper, we present a successful example of employing structure-based virtual screening, a method that combines shape-based database search with a docking study and analogue search, to discover a novel family of PPARγ agonists based upon pyrazol-5-ylbenzenesulfonamide. Two analogues in the family show high affinity for, and specificity to, PPARγ and act as partial agonists. They also demonstrate glucose-lowering efficacy in vivo. A structural biology study reveals that they both adopt a distinct binding mode and have no H-bonding interactions with PPARγ. The absence of H-bonding interaction with the protein provides an explanation why both function as partial agonists since most full agonists form conserved H-bonds with the activation function helix (AF-2 helix) which, in turn, enhances the recruitment of coactivators. Moreover, the structural biology and computer docking studies reveal the specificity of the compounds for PPARγ could be due to the restricted access to the binding pocket of other PPAR subtypes, i.e., PPARR and PPARδ, and steric hindrance upon the ligand binding.
Journal of Biomolecular Structure and Dynamics, 2019
Diabetes is a foremost health problem globally susceptible to increased mortality and morbidity. The present therapies in the antidiabetic class have sound adverse effects and thus, emphasis on the further need to develop effective medication therapy. Peroxisome proliferator-activated receptor alpha-gamma dual approach represents an interesting target for developing novel anti-diabetic drug along with potential anti-hyperlipidimic activity. In the current study, the peroxisome proliferator-activated receptor alpha-gamma agonistic hits were screened by hierarchical virtual screening of drug like compounds followed by molecular dynamics simulation and knowledge-based structure-activity relation analysis. The key amino acid residues of binding pockets of both target proteins were acknowledged as essential and were found to be associated in the key interactions with the most potential dual hit. This dual targeted approach of structure based computational technique was undertaken to identify prevalent promising hits for both targets with binding energy and absorption distribution metabolism excretion prediction supported the analysis of their pharmacokinetic potential. In addition, stability analysis using molecular dynamics simulation of the target protein complexes was performed with the most promising dual targeted hit found in this study. Further, comparative analysis of binding site of both targets was done for the development of knowledge-based structure-activity relationship, which may useful for successful designing of dual agonistic candidates.
Journal of Computer-Aided Molecular Design, 2011
Peroxisome Proliferator-Activated Receptor c (PPARc) full agonists are molecules with powerful insulinsensitizing action that are used as antidiabetic drugs. Unfortunately, these compounds also present various side effects. Recent results suggest that effective PPARc agonists should show a low transactivation activity but a high binding affinity to inhibit phosphorylation at Ser273. We use several structure activity relationship studies of synthetic PPARc agonists to explore the different binding features of full and partial PPARc agonists with the aim of differentiating the features needed for binding and those needed for the transactivation activity of PPARc. Our results suggest that effective partial agonists should have a hydrophobic moiety and an acceptor site with an appropriate conformation to interact with arm II and establish a hydrogen bond with Ser342 or an equivalent residue at arm III. Despite the fact that interactions with arm I increase the binding affinity, this region should be avoided in order to not increase the transactivation activity of potential PPARc partial agonists.
Journal of Medicinal Chemistry, 2008
The peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors regulating glucose and lipid metabolism. The search for new PPAR ligands with reduced adverse effects with respect to the marketed antidiabetic agents thiazolidinediones (TZDs) and the dual-agonists glitazars is highly desired. We report the crystal structure and activity of the two enantiomeric forms of a clofibric acid analogue, respectively complexed with the ligand-binding domain (LBD) of PPARγ, and provide an explanation on a molecular basis for their different potency and efficacy against PPARγ. The more potent S-enantiomer is a dual PPARR/PPARγ agonist which presents a partial agonism profile against PPARγ. Docking of the S-enantiomer in the PPARR-LBD has been performed to explain its different subtype pharmacological profile. The hypothesis that partial agonists show differential stabilization of helix 3, when compared to full agonists, is also discussed. Moreover, the structure of the complex with the S-enantiomer reveals a new region of the PPARγ-LBD never sampled before by other ligands.
Structure-based identification of novel PPAR gamma ligands
Bioorganic & Medicinal Chemistry Letters, 2013
Peroxisome proliferator-activated receptor c (PPARc) is a nuclear receptor with an important role in the glucose metabolism and a target for type 2 diabetes mellitus therapy. The recent findings relating the use of the receptor full agonist rosiglitazone and the incidence of myocardial infarction raised concerns regarding whether receptor activation can actually be useful for diabetes management. The discovery of MRL-24 and GQ-16, ligands that can partially activate PPARc and prevent weight gain and fluid retention, showed that a submaximal receptor activation can be a goal in the development of new ligands for PPARc. Additionally, two previously described receptor antagonists, SR-202 and BADGE, were also shown to improve insulin sensitivity and decrease TNF-a level, revealing that receptor antagonism may also be an approach to pursue. Here, we used a structure-based approach to screen the subset 'Drugs-Now' of ZINC database. Fifteen ligands were selected after visual inspection and tested for their ability to bind to PPARc. A benzoimidazol acetate, a bromobenzyl-thio-tetrazol benzoate and a [[2-[(1,3-dioxoinden-2-ylidene)methyl]phenoxy]methyl]benzoate were identified as PPARc ligands, with IC 50 values smaller than 10 lM. Molecular dynamic simulations showed that the residues H323, H449, Y327, Y473, K367 and S289 are key structural elements for the molecular recognition of these ligands and the polar arm of PPARc binding pocket.