Simultaneous Pharmacokinetics Estimation of Nateglinide and Pioglitazone by RP-HPLC: Computational Study to Unlock the Synergism.

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.

Exploring molecular structural requirement for AChE inhibition through multi-chemometric and dynamics simulation analyses.

The acetylcholinesterase enzyme (AChE) plays an important role in central and peripheral nervous systems. Acetylcholine (ACh) acts through the regulation of AChE activity, which can play a key role in accelerating senile amyloid ß-peptide (Aß) plaque deposition. Therefore, inhibition of the AChE enzyme can be used as a key principle to prevent ACh depletion. The present study has been emphasized to explore both ligand- and structure-based 3D QSAR, HQSAR, pharmacophore, molecular docking and simulation studies on a set of structurally diverse inhibitors to optimize prime structural features responsible for selective binding to AChE, and vis-à-vis inhibiting enzyme activity. The pharmacophore model showed the importance of HB acceptor and donor, positive ionization and hydrophobic features of the molecule for effective binding. Structure-based docking and simulation studies adjudged the significance of features obtained from ligand-based 3D QSAR, CoMFA (Q2 = .608, [Formula: see text] = .700), CoMSIA (Q2 = .632, [Formula: see text] = .734), HQSAR (Q2 = .850, [Formula: see text] = .693) and pharmacophore (Q2 = .839, ROCscore = .769) models. The aim of the present study is to identify the essential structural and physicochemical profiles of molecules that can provide therapeutic benefits with less toxicity. Structurally diverse compounds have been used for the study, and the generated models showed the large applicability domain.

Exploring Structural and Physicochemical Profiles of Potential GSK-3ß Inhibitors Using Structure- and Ligand-Based Modeling Studies.

Glycogen synthase kinase-3ß (GSK-3ß) is a promising target for therapeutic invasion of Alzheimer's disease (AD). The kinase enzyme plays major role in pathological process for the formation of ß-amyloid plaques and neurofibrillary tangles in AD. In the present study, structure-based pharmacophore and ligand-based 3D QSAR, HQSAR and pharmacophore mapping studies have been emphasized to explore the possible structural requirement of this potential kinase inhibitors using a structurally diverse set of compounds. The developed models were validated with the interaction study at the catalytic cleft. The 3D QSAR studies yield robust models of CoMFA R(2) = 0.965, se = 0.212, Q(2) = 0.525, R(2)pred = 0.709, r(2)m = 0.579 and CoMSIA: R(2) = 0.935, se = 0.289, Q(2) = 0.581, R(2)pred = 0.723, r(2)m = 0.935, that explain the importance of steric, electrostatic, hydrogen bond (HB) acceptor of the molecule for inhibition of GSK-3ß. The HQSAR study (R(2) = 0.871, se = 0.400, Q(2) = 0.639, R(2)pred = 0.721, r(2)m = 0.664) indicated the fragments of the molecular fingerprints that might be important for inhibition. Both structure- and ligand-based pharmacophore mapping proposed that acceptor and donor features of the molecule are essential for receptor-ligand interactions. Molecular diversity provides an opportunity on wide range of applicability for the GSK-3ß inhibitors, and depicts information on the structural and properties requirement for effective binding at the active site selectivity that minimize the side effects with therapeutic benefits.

Chemometric design to explore pharmacophore features of BACE inhibitors for controlling Alzheimer's disease.

The ß-amyloid precursor protein cleavage enzyme (BACE) has been conceived to be an attractive therapeutic target to control Alzheimer's disease (AD). Validated ligand-based pharmacophore mapping was combined with 3D QSAR modeling approaches that include CoMFA, CoMSIA and HQSAR techniques to identify structural and physico-chemical requirements for a potential BACE inhibitor using a database containing 980 structurally diverse compounds, assembled from different reports. A structure-based docking technique was also used to validate the features obtained from the ligand-based models, which were further used to screen the database of compounds designed by a de novo approach. Contour maps of 3D QSAR models, CoMFA (R(2) = 0.880, se = 0.402, Q(2) = 0.596, Rpred(2) = 0.713,) and CoMSIA (R(2) = 0.903, se = 0.362, Q(2) = 0.578, Rpred(2) = 0.715), and a pharmacophore space model (R(2) = 0.833, rmsd = 1.578, Q(2) = 0.845, Rpred(2) = 0. 764) depict that the models are robust and provide an explanation of the important features such as steric, electrostatic, hydrophobic, positive ionization, hydrogen bond acceptor and donor properties, which play important roles for interaction with the receptor site cavity. The HQSAR study (R(2) = 0.823, se = 0.488, Q(2) = 0.823, Rpred(2) = 0.768) and de novo design, which generate new fragments, illustrated the important molecular fingerprints for inhibition. The docking study elucidated the important interactions between the amino acid residues (Gly11, Thr72, Asp228, Gly230, Thr231, Arg235) at the catalytic site of the receptor and the ligand, indicating the structural requirements of the inhibitors. The de novo designed molecules were further screened for ADMET properties, and ligand-receptor interactions of the top hits were analysed by molecular docking to explore pharmacophore features of BACE inhibitors.

Molecular modeling on structure-function analysis of human progesterone receptor modulators.

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): n(Tr)=100, R(2) (pred)=0.702; test set (Ts): n(Ts)=30, R(2) (pred)=0.705, R(2) (m)=0.635; validation set (Vs): n(Vs)=40, R(2) (pred)=0.715, R(2) (m)=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: n(Tr)=26, Q(2)=0.927; Ts: n(Ts)=60, R(2) (pred)=0.613, R(2) (m)=0.545; Vs: n(Vs)=84, R(2) (pred)=0.611, R(2) (m)=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.