Department of Pharmacy
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Item Molecular Electrostatic Potentials in the Design of Dendrimers for the Delivery of Glitazones(American Scientific Publishers, 2006) Sundriyal, SandeepGlitazones are PPARγ agonistic insulin sensitizers used clinically for the treatment of type-2 diabetes. The delivery of these compounds with the help of dendrimers is possible. Ab initio MO calculations and MESP analysis indicate that the dendrimers with complementary electrostatic potential to glitazones can be designed. The estimated binding strength between one arm of dendrimer and thiazolidinedione is about 15–20 kcal/mol. This binding strength originates from three hydrogen bonds between the dendrimer and each molecule of glitazone. This binding strength is quite suitable for drug encapsulation on the dendrimer based nanoparticles and can be employed for drug delivery.Item Metformin and glitazones: does similarity in biomolecular mechanism originate from tautomerism in these drugs?(Wiley, 2007-11) Sundriyal, SandeepThis theoretical study attempts to find out similarity between metformin and glitazone class of antidiabetic drugs. It was found that some tautomeric forms of both metformin and thiazolidinedione ring of glitazones have similar molecular electrostatic potential (MESP) surface and may bind to a common complementary surface. Complexation and docking studies were also carried out in order to support this hypothesis.Item Minimum requirements of hydrophobic and hydrophilic features in cationic peptide antibiotics (CPAs): pharmacophore generation and validation with cationic steroid antibiotics (CSAs)(Springer, 2008-02) Sundriyal, SandeepCationic peptide antibiotics (CPAs) are known to possess amphiphilic structure, by virtue of which they display lytic activity against bacterial cell membranes. Naturally occurring antimicrobial peptides contain a large number of amino acid residues, which limits their clinical applicability. Recent studies indicate that it is possible to decrease the chain-length of these peptides without loss of activity, and suggest that a minimum of two positive ionizable (hydrophilic) and two bulky groups (hydrophobic) are required for antimicrobial activity. By employing the HipHop module of the software package CATALYST, we have translated these experimental findings into 3-D pharmacophore models by finding common features among active peptides. Positively ionizable (PI) and hydrophobic (HYD) features are the important characteristics of compounds used for pharmacophore model development. Based on the highest score and the presence of amphiphilic structure, two separate hypothesis, Ec-2 and Sa-6 for Escherichia coli and Staphylococcus aureus, respectively, were selected for mapping analysis of active and inactive peptides against these organisms. The resulting models not only provided information on the minimum requirement of PI and HYD features but also indicated the importance of their relative arrangement in space. The minimum requirement for PI features was two in both cases but the number of HYD features required in the case of E. coli was four while for S. aureus it was found to be three. These hypotheses were able to differentiate between active and inactive CPAs against both organisms and were able to explain the experimental results. The hypotheses were further validated using cationic steroid antibiotics (CSAs), a different class of facial amphiphiles with same mechanism of antimicrobial action as that of CPAs. The results showed that CSAs also require similar minimum features to be active against both E. coli and S. aureus. These studies also indicate that the minimum feature requirements may be conserved for different strains of the same organism.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 Antimicrobial Hexapeptides: Synthesis, Antimicrobial Activities, Cytotoxicity, and Mechanistic Studies(Wiley, 2009-12) Sundriyal, SandeepThe lead optimization of an antimicrobial hexapeptide Orn-D-Trp-D-Phe-Ile-D-Phe-His(1-Bzl)-NH2 depending on the hydrophobic or positive-charge character of amino acids at various positions along its sequence was performed, followed by biological evaluation and mechanistic studies. This led to the identification of a new class of antimicrobial hexapeptides that interact preferentially with the negatively charged phospholipids of a model bacterial membrane.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 Modeling and Informatics in Designing Anti-Diabetic Agents(Bentham Science, 2007) Sundriyal, SandeepDiabetes mellitus is a chronic metabolic disorder, characterized by glucose overproduction and glucose underutilization. Current therapy for T2DM includes drugs, like metformin, glitazones, sulphonyl ureas, etc. Extensive research has been carried out world wide on molecular targets for T2DM like PPARγ, PTP1B, DPP-IV, GSK-3, cannabinoid receptor, fructose-bisphosphatases, β3 adrenoceptor, etc. in the development of newer anti-diabetic agents. These therapeutic targets are quite important and most of them are suitable for in silico analysis. Hence, many molecular modeling and informatics studies like, molecular docking, pharmacophore mapping, 3DQSAR, virtual screening, quantum chemical studies, and pharmacoinformatics like bioinformatics and chemoinformatics studies have been performed on the drugs / leads / targets associated with T2DM. Several of these in silico efforts are exemplary studies; the methodologies adopted in these studies can be emulated in many other therapeutic areas. A review of the rational approaches reported in designing anti-diabetic agents is presented in this article.Item Coordination Chemistry Based Approach to Lipophilic Inhibitors of 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase(ACS, 2009-10) Sundriyal, Sandeep1-Deoxy-d-xylulose-5-phosphate reductoisomerase (DXR) in the non-mevalonate pathway found in most bacteria is a validated anti-infective drug target. Fosmidomycin, a potent DXR inhibitor, is active against Gram-negative bacteria. A coordination chemistry and structure based approach was used to discover a novel, lipophilic DXR inhibitor with an IC50 of 1.4 μM. It exhibited a broad spectrum of activity against Gram-negative and -positive bacteria with minimal inhibition concentrations of 20−100 μM (or 3.7−19 μg/mL).