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Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) plays an essential role in lipid and glucose homeostasis. It is recognized as the receptor of the thiazolidinediones-a synthetic class of anti-diabetic drugs-and is the target of many drug discovery efforts because of its role in disease states, such as type II diabetes mellitus. In this study,(More)
We modelled the N-terminal ligand-binding domain of the rho1 GABA(C) receptor based on the Lymnaea stagnalis acetylcholine-binding protein (L-AChBP) crystal structure using comparative modelling and validated using flexible docking guided by known mutagenesis studies. A range of known rho1 GABA(C) receptor ligands comprising seven full agonists, 10 partial(More)
The tyrosine kinase inhibitor drug sorafenib is used in the treatment of liver and renal cancers but adverse effects may necessitate dose interruption and under-dosage may lead to therapeutic failure. Sorafenib also undergoes cytochrome P450 (CYP)-dependent biotransformation to the N-oxide and other metabolites. However, although CYPs are major determinants(More)
Aurora kinase inhibitors are new mitosis-targeting drugs currently in clinical trials for the treatment of haematological and solid malignancies. However, knowledge of the molecular factors that influence sensitivity and resistance remains limited. Herein, we developed and characterised an in vitro leukaemia model of resistance to the Aurora B inhibitor(More)
Gamma-aminobutyric acid (GABA) analogues based on 4-amino-cyclopent-1-enyl phosphinic acid ( 34- 42) and 3-aminocyclobutane phosphinic acids ( 51, 52, 56, 57) were investigated in order to obtain selective homomeric rho 1 GABA C receptor antagonists. The effect of the stereochemistry and phosphinic acid substituent of these compounds on potency and(More)
The tyrosine kinase inhibitors (TKIs) and multikinase inhibitors (MKIs) are oncology drugs of increasing importance that have improved the treatment of multiple tumors types. In some patients these agents produce adverse effects, including pharmacokinetic drug-drug interactions, due to cytochrome P450 (CYP) inhibition. Information on the propensity of the(More)
The effect of cholesterol removal by methyl-beta-cyclodextrin on the dipole potential, psi(d), of membrane vesicles composed of natural membrane lipids extracted from the kidney and brain of eight vertebrate species was investigated using the voltage-sensitive fluorescent probe di-8-ANEPPS. Cyclodextrin treatment reduced cholesterol levels by on average 80%(More)
Synthetic cannabinoid (SC) designer drugs featuring bioisosteric fluorine substitution are identified by forensic chemists and toxicologists with increasing frequency. Although terminal fluorination of N-pentyl indole SCs is sometimes known to improve cannabinoid type 1 (CB1) receptor binding affinity, little is known of the effects of fluorination on(More)
Accurate structure factors have been measured for the two known conformational polymorphs (A and B) of famotidine up to a maximum resolution of sin(theta)/lambda = 1.2 A(-1) at 100 K using a conventional X-ray source and a CCD-based diffractometer. The experimental electron-density distribution was modelled using a multipole model and the interatomic(More)
The suitability of a hybrid density functional to qualitatively reproduce geometric and energetic details of parallel pi-stacked aromatic complexes is presented. The hybrid functional includes an ad hoc mixture of half the exact (HF) exchange with half of the uniform electron gas exchange, plus Lee, Yang, and Parr's expression for correlation energy. This(More)