Discovery of Novel PPAR Ligands by a Virtual Screening Approach Based on Pharmacophore Modeling, 3D Shape, and Electrostatic Similarity Screening

Abstract

Peroxisome proliferator-activated receptors (PPARs) are important targets for drugs used in the treatment of atherosclerosis, dyslipidaemia, obesity, type 2 diabetes, and other diseases caused by abnormal regulation of the glucose and lipid metabolism. We applied a virtual screening workflow based on a combination of pharmacophore modeling with 3D shape and electrostatic similarity screening techniques to discover novel scaffolds for PPAR ligands. From the resulting 10 virtual screening hits, five tested positive in human PPAR ligand-binding domain (hPPAR-LBD) transactivation assays and showed affinities for PPAR in a competitive binding assay. Compounds 5, 7, and 8 were identified as PPAR-alpha agonists, whereas compounds 2 and 9 showed agonistic activity for hPPAR-gamma. Moreover, compound 9 was identified as a PPAR-delta antagonist. These results demonstrate that our virtual screening protocol is able to enrich novel scaffolds for PPAR ligands that could be useful for drug development in the area of atherosclerosis, dyslipidaemia, and type 2 diabetes.

Pan‐PPAR Agonists Based on the Resveratrol Scaffold: Biological Evaluation and Docking Studies

“…Some PPAR agonists with a branched hydrophobic moiety are able to interact with both hydrophobic arms. [18] GW409544 is a full PPARa and PPARg agonist. [19] GW409544 was mainly docked into arms I and II of the binding pocket of PPARa, while 6 was docked into arms I and III.…”

Pharmacophore Models for Virtual Screening

“…Among these enrichment metrics, the EF and the AUC value, as well as visualizations of ROC curves, represent popular methods for assessing the enrichment of active molecules by pharmacophore models [83][84][85]. The two disadvantages of many of these enrichment metrics are the lack of information about early enrichment of active molecules and the missing comparability between validation results gained by screening molecule databases with different ratio of actives.…”

“…However, the lack of conformer-to-model fitting produces a larger hit list containing lots of molecules that would not fall within the tolerance radii of the model features if an alignment would be performed. Thus, a DS CATALYST hit list filtered by the optional alignment and ranked by the fit value was the basis of several published VS studies aiming at the discovery of novel, biologically active ligands [85,[93][94][95][96].…”

Cytotoxic Activities of Amentoflavone against Human Breast and Cervical Cancers are Mediated by Increasing of PTEN Expression Levels due to Peroxisome Proliferator-Activated Receptor γ Activation

“…Recently, it has been reported that an antagonist of PPARδ is effective against cancer; therefore, PPARδ could be a target in cancer therapy. 10 PPARγ, the most wellknown PPAR, is present in adipocytes in high concentrations. Because it is highly expressed in adipocytes, PPARγ has long been considered a typical therapeutic target for type-2 diabetes.…”