No abstract

Considering the significance of progesterone receptor (PR) modulators, the present study is explored to envisage the biophoric signals for binding to selective PR subtype-A using ligand-based quantitative structure activity relationship (QSAR) and pharmacophore space modeling studies on nonsteroidal substituted quinoline and cyclocymopol monomethyl ether derivatives. Consensus QSAR models (Training set (Tr): nTr=100, R2pred=0.702; test set (Ts): nTs=30, R2pred=0.705, R2m=0.635; validation set (Vs): nVs=40, R2pred=0.715, R2m=0.680) suggest that molecular topology, atomic polarizability and electronegativity, atomic mass and van der Waals volume of the ligands have influence on the presence of functional atoms (F, Cl, N and O) and consequently contribute significant relations on ligand binding affinity. Receptor independent space modeling study (Tr: nTr=26, Q2=0.927; Ts: nTs=60, R2pred=0.613, R2m=0.545; Vs: nVs=84, R2pred=0.611, R2m=0.507) indicates the importance of aromatic ring, hydrogen bond donor, molecular hydrophobicity and steric influence for receptor binding. The structure-function characterization is adjudged with the receptor-based docking study, explaining the significance of the mapped molecular attributes for ligand-receptor interaction in the catalytic cleft of PR-A.

Inhibition of the neurotransmitter acetylcholine (ACh) can control the alzheimer's disease (AD). The ACh hydrolyzes to produce choline and acetyl groups through acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in the synaptic region, which play a key role in accelerating senile amyloid β-peptide (Aβ) plaque depositions, leads to generation of AD. The present study has been emphasized to explore both ligand-and structure-based QSAR and docking studies on a set of structurally diverse compounds to explore prime structural features responsible for selective binding to AChE, visa -vis inhibiting enzyme activity. Both the studies showed the importance of HB acceptor and donor, and hydrophobic features of the molecule for effective binding. Systematic comparisons revealed that structure-based study has advantages in efficiently identifying potent hits with structural diversity over simple ligand-based study. Structure-based QSAR study (site score = 1.006) adjudged the significance of features obtained from ligand-based QSAR model (ROC score = 0.850, sensitivity = 0.710, specificity = 0.932). Presence of electronegative groups, and acyclic and aromatic rings in the molecular scaffold depict the importance in selective AChE inhibition.

Nateglinide (NAT) and Pioglitazone (PIO) are an antidiabetic drugs combination and currently under clinical trial in countries like Japan. In this study, an alternative, a simple, sensitive high-performance liquid chromatography method has been developed (limit of detection: 15 ng/mL and limit of quantification: 50 ng/mL) for simultaneous estimation of this drug combination in rat plasma. Most remarkably, bioavailability of NAT has been increased markedly on coadministration with PIO, than when it was administered alone. Thus, PIO is assumed to retard the catabolism of NAT by inhibiting metabolic liver-microsomal enzyme, especially CYP2C9. Using a Waters Nova-Pak C 18 column (150 × 3.9 mm, 4 μm) and a mobile phase of acetonitrile: 10 mM KH2PO4 (60: 40, V/V (volume by volume)) pH 3.5, the analysis was performed at 210 nm with a flow rate of 1.5 mL/min. In silico docking via molecular dynamics simulation revealed that NAT-CYP2C9 binding affinity may be reduced after PIO attachment, presumably due to the binding site overlapping of the two drugs. Thus, it has been proposed that NAT and PIO may be an efficient synergistic fixed dose combination against diabetes mellitus, and the above method can foster a simple but highly sensitive bioanalytical estimation for routine analysis.

No abstract