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.
Abhirami Pv, Gupta Dheeraj Rajesh, N. V. L. Sirisha Mulukuri et al.· Frontiers in Bioinformatics· 0 citations
The Alzheimer's Disease (AD) lacks effective disease-modifying therapy, even though amyloid-targeting immunotherapies have recently been applied clinically. N-methyl-D-Aspartate Receptors (NMDARs) play a central yet mechanistically complicated role in the pathophysiology of AD, where they are convergence points of amyloid-beta (Aβ) oligomer toxicity, tau-dependent excitotoxicity, and progressive synaptic failure. This critical review examines NMDAR dysfunction across the AD spectrum, with a focus on subunit-regulated signalling, subcellular localisation, and subsequent pathological cascades. The effects of Aβ oligomers on NMDAR activity involve multiple mechanisms that disrupt their function, including glutamate dysregulation mediated by GLT-1, redistribution of GluN2B to extrasynaptic areas, and inhibition of JAK2-CREB via activation of extrasynaptic receptors. Tau enhances excitotoxic injury throughdendritic mislocalization, and the tau-Fyn-GluN2B complex, which propels pro-death signalling by DAPK1. This conceptually important prevailing synaptic-extrasynaptic dichotomy is fiercely criticised here, given evidence that synaptic receptors containing GluN2A also mediate pathological signalling during sustained Aß exposure, and that tri-heteromeric receptor populations are problematic for subunit-selective targeting. Neuroinflammation, dysfunction of the blood-brain barrier, and excitotoxic amplification via GluN2C/D-enriched receptor pools in neurons, astrocytes, microglia, oligodendrocytes, and endothelial cells are underexplored therapeutic targets for neurodegenerative disease (non-neuronal NMDARs). Memantine is the only approved NMDAR-targeting agent for AD. Subunit-selective antagonists have not been translated into clinical use, and the positive allosteric modulator dalzanemdor (SAGE-718) did not pass its randomised Phase 2 trial in 2024. The most mechanistically justified approach is to advance subunit-selective, compartment-specific, or protein-complexdisrupting strategies. Although it is not established whether any single NMDAR-targeting intervention will suffice as a disease-modifying therapy, the convergence of molecular, genetic, and clinical evidence positions NMDAR dysfunction as a tractable , if therapeutically demanding , node in the AD pathogenic network, warranting continued, mechanism-informed drug discovery.
Md Sirajuddin Khan, A. M. Ashesh, Mithul V. Mammen et al.· Current Neuropharmacology· 0 citations
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