Department of Pharmacy
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Item Identification of antimalarial leads with dual falcipain-2 and falcipain-3 inhibitory activity(Elsevier, 2020-01) Sundriyal, SandeepFalcipains (FPs), cysteine proteases in the malarial parasite, are emerging as the promising antimalarial drug targets. In order to identify novel FP inhibitors, we generated a pharmacophore derived from the reported co-crystal structures of inhibitors of Plasmodium falciparum Falcipain-3 to screen the ZINC library. Further, the filters were applied for dock score, drug-like characters, and clustering of similar structures. Sixteen molecules were purchased and subject to in vitro enzyme (FP-2 and FP-3) inhibition assays. Two compounds showed in vitro inhibition of FP-2 and FP-3 at low µM concentration. The selectivity of the inhibitors can be explained based on the predicted interactions of the molecule in the active site. Further, the inhibitors were evaluated in a functional assay and were found to induce morphological changes in line with their mode of action arresting Plasmodium development. Compound 15 was most potent inhibitor identified in this study.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).Item QSAR and Docking Studies of N-hydroxy Urea Derivatives as Flap Endonuclease-1 Inhibitors(Bentham Science, 2015) Jadhav, Hemant R.Flap endonuclease-I (FEN-1) is involved in DNA repair and considered to be a novel target for the development of anticancer agents. N-hydroxy urea derivatives have been reported as FEN-1 inhibitors. To derive in vitro and in silico correlation, we have performed 2D-quantitative structure activity relationship (QSAR) analysis and docking studies on these compounds. 2D-QSAR models were developed using multiple linear regression (MLR) analysis and cross-validation using leave one out (LOO) method. The best model displayed R2 of 0.806 and Q2 of 0.607. Docking study revealed key interactions with desired amino acids and compare well with the in vitro potency of the reported compounds. Both studies reveal a link between FEN-1 inhibition and physicochemical descriptors or interactions with amino acids in active site. The information generated is first of its kind and may be helpful in the design of novel FEN-1 inhibitors.