Benzoxazinones as human peroxisome proliferator activated receptor gamma (PPARγ) agonists: A docking study using glide (original) (raw)
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The synthetic and docking studies of 2-Methylchromonyl linked para/meta substituted phenyl containing thiazolidenedione (TZD), diethyl malonate (DEM), methyl acetoacetate (MAA), barbituric acid (BA) and thiobarbituric acid (TBA) analogues in an effort to develop novel peroxisome proliferator activated receptors ligands expected to exhibit PPAR? partial agonism in the management of hyperglycemia and hyperlipidemia for the treatment of type 2 diabetes is reported. Docking studies showed expected results.
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.
Bioorganic & Medicinal Chemistry, 2019
We previously identified dibenzooxepine derivative 1 as a potent PPARγ ligand with a unique binding mode owing to its non-thiazolidinedione scaffold. However, while 1 showed remarkably potent MKN-45 gastric cancer cell aggregation activity, an indicator of cancer differentiation-inducing activity induced by PPARγ activation, we recognized that 1 was metabolically unstable. In the present study, we identified a metabolically soft spot, and successfully discovered 3-fluoro dibenzooxepine derivative 9 with better metabolic stability. Further optimization provided imidazo[1,2-a]pyridine derivative 17, which showed potent MKN-45 gastric cancer cell aggregation activity and excellent PK profiles compared with 9. Compound 17 exerted a growth inhibitory effect on AsPC-1/AG1 pancreatic tumor in mice. Furthermore, the decrease in the hematocrit (an indicator of localized edema, a serious adverse effect of PPARγ ligands) was tolerable even with oral administration at 200 mg/kg in healthy mice.
Journal of Pharmaceutical Chemistry, 2017
Peroxisome proliferated receptors (PPARs) are important targets for drugs used in the treatment of various metabolic disorders. We have reported 4-hydroxy benzylidene derivatives of thiazolidine-2,4-diones with reversed orientation in the active site of PPARγin our earlier communication. With the reversed conformation of TZD, fitting the established pharmacophore was discussed. The current simulation studies revolves around the 2,4-dihydroxy benzylidene derivatives expecting H-bonding interactions similar to Rosiglitazone’s acidic head. The docking protocol was validated by enrichment studies using decoys and actives from DUD. Designed compounds were showing interactions similar to the actives in the top 10%, 5% and 1%. They also exhibited H-bonding interactions similar to their monohydroxy counterparts without any additional H-bonding interactions due to introduction of additional hydroxy functional groups. Predicted ADMET report reveals that 5 molecules show favourable hERG-I a...
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.
Lipids in Health and Disease
Background: The use of statin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor for the treatment of dyslipidemia has been associated with dose limiting hepatoxicity, mytotoxicity and tolerability due to myalgias thereby necessitating the synthesis of new drug candidates for the treatment of lipid disorder. Methods: The reaction of appropriate benzenesulphonamide with substituted phenoxazinone in the presence of phenylboronic acid gave the targeted compounds. The molecular docking study were carried out using autodock tool against peroxisome proliferator activated receptor alpha. The in vivo lipid profile were assayed using conventional methods. The kidney and liver function test were carried out to assess the effect of the derivatives on the organs. The LD 50 of the most active derivatives were determined using mice. Results: The targeted compounds were successfully synthesized in excellent yields and characterized using spectroscopic techniques. The results of the molecular docking experiment showed that they were good stimulant of peroxisome proliferator activated receptor alpha. Compound 9f showed activity at Ki of 2.8 nM and binding energy of 12.6 kcal/mol. All the compounds tested reduced triglyceride, total cholesterol, low density lipoprotein cholesterol and very low density lipoprotein cholesterol level in the mice model. Some of the reported compounds also increased high density lipoprotein cholesterol level in the mice. The compounds did not have appreciable effect on the kidney and liver of the mice used. The LD 50 showed that the novel compounds have improved toxicity profile. Conclusion: The synthesis of fifteen new derivatives of carboxamides bearing phenoxazinone and sulphonamide were successful. The compounds possessed comparable activity to gemfibrozil. The reported compounds had better toxicity profile than gemfibrozil and could serve as a replacement for the statins and fibrate class of lipid agents.
Flexible ligand recognition of peroxisome proliferator-activated receptor-? (PPAR?)
Bioorg Medicinal Chem Letter, 2010
The peroxisome proliferator-activated receptor-γ (PPARγ) is a direct pharmacological target for drugs that enhance insulin sensitivity and are used clinically for the treatment of type II diabetes. Because the specificity of ligand recognition is lower for PPARγ than for other nuclear receptors, PPARγ can bind a larger variety of ligand types. In order to elucidate why the ligand recognition of PPARγ is so flexible, we performed correlated fragment molecular orbital calculations for complexes of PPARγ and each of two distinctive ligands, rosiglitazone and farglitazar. We found quite different patterns of ligand binding for these two ligands. The ligand-binding system of rosiglitazone, a drug in common clinical use, is based mainly on local electrostatic interactions around the thiazolidine ring, whereas both electrostatic interactions and van der Waals dispersion interactions with hydrophobic residues are required for the binding of farglitazar to PPARγ. We suggest that the development of novel ligands will require adequately hydrophobic pharmacophores.The large LBP of PPARγ permits different binding systems for typical ligands, and the development of novel ligands of sufficient binding affinity will require adequately hydrophobic pharmacophores.
Journal of Proteomics & Bioinformatics
Peroxisome Proliferator-Activated Receptor Gamma encoded by PPARG gene is also known as type II nuclear receptor in humans plays a significant role in regulating the glucose metabolism, adipocyte differentiation and serves as a lipid sensor. This has been implicated in the pathology of various diseases like obesity, diabetes, atherosclerosis, and cancer. In search of drugs that uses PPAR gamma as a therapeutic target for its inhibition: Insilico CADD approaches has been widely used in this aspect to understand the intrinsic molecular aspects and their interaction with the chemicals. In-silico based virtual screening helps in identification of optimum molecule among the large dataset to elucidate the effects on a particular target through binding interaction and can be used for further experimentations. In the present study, two PPAR gamma/antagonists GW9662 and T0070907 were selected for this study as they serves as potent therapeutics to minimize the effects of PPAR gamma in chronic diseases. A set of structural analogs of GW9662 and T0070907 were screened from ZINC public database. Ligand based screening is followed by 80% similarity search, Lipinski filter, Pharmacophore based and toxicity based screening. Structure based virtual screening follows the output and final molecular docking using iGemdock and Autodock explained the binding affinity and pharmacological interactions. The results between the GW9662, T0070907 and screened structural analogs show better binding affinity with respect to the former one with similar pharmacological interactions.
Bioorganic & Medicinal Chemistry, 2010
In this and previous studies we investigated the importance of partial structures of Telmisartan on PPARc activation. The biphenyl-4-ylmethyl moiety at N1 and residues at C2 of the central benzimidazole were identified to be essential for receptor activation and potency of receptor binding. Now we focused our attention on positions 5 and 6 of the central benzimidazole and introduced bromine (3b-5/6, 3c), phenylcarbonyl (3d-5/6), hydroxy(phenyl)methyl (3g-5/6), hydroxymethyl (3h-5/6) and formyl (3i) groups. The selection of these moieties was inspired by the structure of Losartan and its metabolite EXP3179. In order to increase the hydrophobicity of the central part of the molecule, the benzimidazole was exchanged by a naphtho[2,3-d]imidazole (5). The compounds 3a-3i and 5 were tested in a differentiation assay using 3T3-L1 preadipocytes and a luciferase assay using COS-7 cells, transiently transfected with pGal4-hPPARcDEF, pGal5-TK-pGL3 and pRL-CMV, as established models for the assessment of cellular PPARc activation. An enhanced effect on PPARc activation could be observed if lipophilic moieties are introduced in these positions. 4 0 -[(2-Propyl-1H-naphtho[2,3-d]imidazol-1-yl)methyl]biphenyl-2-carboxylic acid (5) was identified as the most potent compound with an EC 50 of 0.26 lM and the profile of a full agonist.