Department of Pharmacy
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Item New PPARγ ligands based on 2-hydroxy-1,4-naphthoquinone: Computer-aided design, synthesis, and receptor-binding studies(Elsevier, 2008-06) Sundriyal, SandeepFlexX-based molecular docking study was employed to identify 2-hydroxy-1,4-naphthoquinone as a new ‘acidic head group’ for the design of a novel series of PPARγ ligands. To provide the proof of concept, designed molecules were synthesized and evaluated in a standard radioligand-binding assay. Out of eight molecules, four were found to bind to the murine PPARγ with IC50 ranging from 0.2 to 56.2 μM as compared to standard pioglitazone, with IC50 of 0.7 μMItem Important pharmacophoric features of pan PPAR agonists: Common chemical feature analysis and virtual screening(Elsevier, 2009-09) Sundriyal, SandeepHipHop program was used to generate a common chemical feature hypothesis for pan Peroxisome Proliferator-Activated Receptor (PPAR) agonists. The top scoring hypothesis (hypo-1) was found to differentiate the pan agonists (actives) from subtype-specific and dual PPAR agonists (inactives). The importance of individual features in hypo-1 was assessed by deleting a particular feature to generate a new hypothesis and observing its discriminating ability between ‘actives’ and ‘inactives’. Deletion of aromatic features AR-1 (hypo-1b), AR-2 (hypo-1e) and a Hydrophobic feature HYD-1 (hypo-1c) individually did not affect the discriminating power of the hypo-1 significantly. However, deletion of a Hydrogen Bond Acceptor (HBA) feature (hypo-1f) in the hydrophobic tail group was found to be highly detrimental for the specificity of hypo-1 leading to high hit rate of ‘inactives’. Since hypo-1 did not produce any useful hits from the database search, hypo-1b, hypo-1c and hypo-1e were used for virtual screening leading to the identification of new potential pan PPAR ligands. The docking studies were used to predict the binding pose of the proposed molecules in PPARγ active site.Item Sum of activities’ as dependent parameter: A new CoMFA-based approach for the design of pan PPAR agonists(Elsevier, 2009-01) Sundriyal, SandeepA ‘sum-model’ (3D QSAR – CoMFA) has been developed to design PPARα/γ/δ (peroxisome proliferator activated receptor) pan agonists by using the sum of activities (EC50) of compounds against individual subtypes as a dependent parameter. In addition, the three subtype specific CoMFA models were also generated using the identical training set molecules (N = 28). All four models were validated using the popular ‘leave-one-out’ (LOO) method and with a test set of 9 molecules. The generated models were found to be statistically significant with rcv2 > 0.5 and rncv2 > 0.9 and the lower values of standard error of estimation (SEE) ranging from 0.097 to 0.160. From the contour map analyses the ‘sum-model’ was found to represent the three subtype specific models and also predicted the sum of activities of the training set molecules with reasonable accuracy. The new molecules were designed based on the ‘sum-model’ and were found to dock well in the PPARγ active site. This approach may find wider applications in the research related to other classes of ‘designed multiple ligands’.Item New PPARγ ligands based on barbituric acid: Virtual screening, synthesis and receptor binding studies(Elsevier, 2008-09) Sundriyal, SandeepA new series of PPARγ ligands based on barbituric acid (BA) has been designed employing virtual screening and molecular docking approach. To validate the computational approach, designed molecules were synthesized and evaluated in in vitro radioligand binding studies. Out of the total 14 molecules, 6 were found to bind to the murine PPARγ with IC50 ranging from 0.1 to 2.5 μM as compared to reference standard, pioglitazone (IC50 = 0.7 μM).