Molecular modeling studies of pyridopurinone derivatives--potential phosphodiesterase 5 inhibitors.

Two- and three-dimensional quantitative structure-activity relationship (QSAR) and docking studies were carried out on a series of pyridopurinones, to model their phosphodiesterase 5 (PDE5) inhibitory activities. 2D-QSAR was performed using the heuristic and best multi linear regression (BMLR) methods in CODESSA (comprehensive descriptors for structural and statistical analysis), which had given linear models between the inhibitory activity and five descriptors of PDE5 inhibitors, with r(2)=0.987, 0.987, q(2)=0.970, 0.970, F=166.71, 166.71 and s(2)=0.0004, 0.0176, respectively. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) have provided statistically significant models with q(2) values of 0.784, 0.742 and r(2) values of 0.975, 0.972 respectively. The predictive ability of the models was validated using a set of 6 compounds that were not included in the training set and the predictive r(2) obtained for the test set was 0.901 and 0.888 respectively. Docking studies were employed to determine the probable binding conformation of these analogues in the PDE5 active site using the programs GOLD and AutoDock whose results were found complementary with 3D-QSAR maps. Since the potency towards PDE5 and the selectivity over PDE6 is important for the successful development of new PDE5 inhibitors, a PDE6 homology model was built using Insight II and Modeller with Phi-Psi BLAST alignment. The molecules were docked in the active site of PDE6 and analyzed the probable reasons for selectivity of these molecules towards PDE5 over PDE6. Mapping the 3D-QSAR models to the active site of PDE5 provides a new insight into the protein-inhibitor interactions and helpful in designing potent and selective PDE5 inhibitors for the treatment of erectile dysfunction.

Homology modeling of membrane proteins: a critical assessment.

Evaluation and validation of homology modeling protocols are indispensable for membrane proteins as experimental determination of their three-dimensional structure is an arduous task. The prediction ability of Modeller, MOE, InsightII-Homology and Swiss-PdbViewer (SPV) with different sequence alignments CLUSTALW, BLAST and 3D-JIGSAW have been assessed. The sequence identity of the target and template was chosen to be in the range of 25-35%. Validation protocols to assess the structure, fold and stereochemical quality, are employed by comparing with experimental structures. Two different ranking schemes are suggested to evaluate the performance of each methodology based on the validation scores. While unambiguous preference for any given procedure did not surface, statistically Modeller and the sequence alignment technique, 3D-JIGSAW, gave best results amongst the chosen protocols. The present study helps in selecting the right protocols when modeling membrane proteins, which form a major class of drug targets.

Recent advances in molecular modeling and medicinal chemistry aspects of phospho-glycoprotein.

Phospho-glycoprotein (P-gp) is an efflux transporter expressed in many organs (ex: kidney, lung, liver and spleen) and in hormone producing or responsive tissues (ex: adrenal cortex, testis and placenta). It is involved in many important physiological functions. Among them the major one is extrusion of xenobiotics in order to detoxify the cells. This property of P-gp is associated with multidrug resistance (MDR) for many pathological conditions. While the experimental determination of three-dimensional structure is not yet successful, the transmembrane (TM) 5, 6, 11 and 12 are sensitive to mutations and contain substrate binding sites. Designing of potential and selective inhibitors of P-gp is still hampered by a lack of information upon the three dimensional structure of P-gp. The design of P-gp inhibitors was traditionally driven by quantitative structure activity relationship studies, which is complicated by factors such as different types of assays, multiple drug binding sites and diverse chemical structures. Clearly a conclusive and predictive SAR does not seem to be practical, despite progress in the last few years towards more specific SAR suggesting well defined structural features responsible for activity. Advances made recently in solving the crystal structure of prokaryotic ATP binding cassette proteins (ABC) transporters, Ec-MsbA, Vc-MsbA and BtuCD yielded suitable templates for construction of homology models of P-gp. Few molecular dynamics (MD) simulations aimed at elucidating the functional dynamics of ABC transporters have provided useful insights to their mechanism and structure. The present review aims at the general overview of importance, expression, structure, organization and drug binding sites of P-gp. This review also highlights recent developments in the homology modeling, molecular dynamics simulations of P-gp and progress in QSAR, pharmacophore modeling of P-gp modulators.

Rhythms of life: antecedents and outcomes of work-family balance in employed parents.

This study examined antecedents and outcomes of a fourfold taxonomy of work-family balance in terms of the direction of influence (work-family vs. family-work) and type of effect (conflict vs. facilitation). Respondents were full-time employed parents in India. Confirmatory factor analysis results provided evidence for the discriminant validity of M. R. Frone's (2003) fourfold taxonomy of work-family balance. Results of moderated regression analysis revealed that different processes underlie the conflict and facilitation components. Furthermore, gender had only a limited moderating influence on the relationships between the antecedents and the components of work-family balance. Last, work-family facilitation was related to the work outcomes of job satisfaction and organizational commitment.