Identification of phillyrin as a PPAR-γ ligand through network pharmacology and molecular modeling.

Design and in silico evaluation of Thiazole–Isoxazole hybrids as PPARγ-Targeted antidiabetic agents

Introduction Diabetes mellitus is a chronic metabolic disorder characterised by persistent hyperglycemia resulting from impaired insulin secretion, action, or both. Prolonged hyperglycemia disrupts metabolic homeostasis and increases the risk of complications, including cardiovascular disease, neuropathy, nephropathy, and retinopathy. Current therapies target multiple pathways but are limited by reduced efficacy and adverse effects. Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of glucose and lipid metabolism and an important therapeutic target. Thiazole and isoxazole scaffolds possess antidiabetic potential, and their hybridisation may improve efficacy and safety. Objective To design and evaluate a novel series of thiazole-linked isoxazole derivatives targeting the alternate ligand-binding domain of PPARγ for potential antidiabetic activity. Result The designed compounds (C1–C210) were docked into PPARγ (Protein Data Bank: 5 GTN), yielding nine candidates with binding affinities of −11.11 to −9.97 kcal/mol. Reference ligands included pioglitazone, Q-35, and S-35, with C139 showing the highest affinity. Molecular dynamics simulations (200 ns) confirmed stability. Advanced Trajectory analyses indicate favourable conformational sampling, correlated residue motions, and a relatively confined conformational space. In silico drug-likeness profiling further supported their activity profile. Conclusion In this computational study, the thiazole-linked isoxazole compound C139 demonstrated probable antidiabetic activity against PPARγ. However, these findings remain predictive and require further validation through comprehensive in vitro and in vivo studies.

Interpretable QSAR modelling for PPAR-γ agonist prediction by integrating a stacking strategy, docking, and MD simulations.

Meta-iPPAR is developed, an integrative in silico framework combining stacked machine learning, molecular docking, and molecular dynamics simulations for the identification of PPAR-γ agonists that will be an effective computational tool for screening and prioritizing potential compounds targeting PPAR-γ in the early stage of drug development pipelines.

Bioisosteric Replacement of Carboxylic Acids in PPAR Agonists: A Mini Review.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate metabolic homeostasis and represent important therapeutic targets for conditions such as type 2 diabetes, dyslipidemia, and cardiovascular disease. While classical modulators often rely on carboxylic acid moieties to anchor receptor binding through hydrogen bonding, such groups are associated with suboptimal pharmacokinetic profiles, including poor bioavailability, rapid metabolism, and limited tissue penetration. This review explores the strategic use of bioisosteres, such as thiazolidinediones, tetrazoles, oxadiazolones, sulfonamides, and acetamides, as alternative polar headgroups in the design of PPAR ligands. We provide an overview of several aspects, highlighting how structural modifications to polar headgroups influence binding modes, receptor selectivity, and agonist profiles in the development of safer and more effective PPAR modulators. Emphasis is placed on synthetic approaches that prioritize convergent, high-yield, and late-stage diversification to facilitate parallel structure-activity relationship (SAR) exploration. Together, these bioisosteric strategies highlight the synergy between medicinal chemistry and synthetic innovation in the pursuit of next-generation PPAR modulators. Future efforts aimed at partial, biased, or tissue-selective agonists will benefit from continued exploration of novel headgroups, enabling safer and more effective therapies for metabolic and inflammatory diseases. Overall, a comparison of the different bioisosteric classes underscores the pivotal role of polar headgroup design in tuning potency, selectivity, and safety, guiding the rational development of future PPAR-targeted therapeutics.

GRAPH NEURAL NETWORK-GUIDED VIRTUAL SCREENING AND CORE-HOPPING-BASED DESIGN OF NOVEL PPAR-γ MODULATORS

An integrated GNN-guided virtual screening and core-hopping workflow tailored specifically to PPAR-γ modulator design is proposed, built around the goal of identifying selective partial agonists and biased ligands that retain insulin-sensitizing efficacy while minimizing helix-12-driven adverse transcriptional programs.

Integrative network pharmacology and molecular dynamics analysis of a curcumin–indole-3-propionic acid conjugate for diabetes-associated cognitive decline

Discovery of Potent and Selective THRβ Agonists Based on an N-Benzoylglycine Scaffold for the Treatment of Metabolic Disorders.

Metabolic disorders, including obesity, dyslipidemia, and metabolic dysfunction-associated steatohepatitis (MASH), pose a growing health burden with limited pharmacological options. Thyroid hormone receptor β (THRβ) is a liver-enriched nuclear receptor that regulates lipid metabolism, mitochondrial function, and energy homeostasis, making it a promising therapeutic target. Guided by structural insights, we designed an N-benzoylglycine scaffold as a new chemotype, which provides selectivity for the THRβ receptor against THRα while preserving key interactions with the arginine-rich positively charged pocket. Conformational restriction was introduced to maintain a near-orthogonal orientation that optimizes ligand insertion and hydrogen-bonding with His435. Among the series, compound 18 (ZG-2585) exhibited potent and selective THRβ activation and favorable pharmacokinetic profiles. In a western-diet-induced metabolic disorder mouse model, oral administration of ZG-2585 improved body weight, hepatic steatosis, and lipid accumulation. These results establish the N-benzoylglycine scaffold as a promising chemotype for developing selective, orally active THRβ agonists for metabolic disorders.