Our laboratory focuses on designing small molecule inhibitors to targets of therapeutic interventions. These inhibitors also serve as molecular probes to understand the etiology of the disease and the role of their target proteins. Additionally our laboratory is developing computational tools to aid drug design and drug delivery.
Current research projects in the laboratory
Develop novel Dopamine D3 receptor selective agonists: The molecular mechanisms underlying the development of L-Dopa induced dyskinesia in Parkinson’s disease are still not well understood. Dyskinesia is accompanied by number of molecular changes including alterations in the levels and signaling of D1, D2 and D3 dopamine receptors. This project focuses on understanding the changes in molecular conformations in D3 receptor with various bound agonists and to develop novel agonists that can modulate unique D3 receptor properties responsible for dyskinesias.
Develop Cardiac glycosides with improved therapeutic indices that inhibit Na+,K+-ATPase: Regulation of sodium and potassium levels in the heart is essential for many physiological functions including electrical excitability, muscle contraction, and cell volume. Inhibition of Na+,K+-ATPase by cardiac glycosides can lead to an increase in cardiac contractility, also called positive inotropic effect, that can be highly effective in improving the contractile performance of the diseased and failing heart. In addition, their cholinergic-like effects on AV nodal conduction also make cardiac glycosides an effective therapy for some supraventricular arrhythmias. However, these drugs, notably clinically useful agents such as digoxin and digitoxin, have a very narrow therapeutic index (1-2nM) that requires careful clinical management to minimize toxic and potentially life-threatening side effects. The goal of this project is to determine the specific structural requirements of the glycoside binding to the Na+,K+-ATPase and to develop novel cardiac glycosides with improved therapeutic indices and high specificity towards Na+,K+-ATPase α1 isoform.
Develop antimalarial compounds that target unique protein-protein interactions: Each year, there are an estimated 250 million cases of malaria worldwide, resulting in almost a million deaths, mostly in young children and pregnant women. Although several drugs are available for treating malaria, widespread resistance to most affordable drugs and the emerging resistance to alternative drugs, as well as their high cost, are major impediments in efforts to control malaria. Clearly, new affordable antimalarials with reduced propensity to develop resistance are needed urgently. Our laboratory has identified two unique chemical scaffolds with antimalarial activities that are likely to work through mechanisms that are distinct from those of currently used antimalarial drugs.
Design Cell Penetrating Peptides for Drug Delivery applications: Advances in drug design and high throughput screening technologies have led to the design of a number of therapeutics and diagnostic agents that target various intracellular molecules. However, biodelivery of these drugs and diagnostic agents to their right target remains a significant challenge. Nearly 30% of all early stage lead molecules that have high affinity to the target determined by in-vitro testing do not make it to clinical trials due to their inability to reach their intended targets. Similarly transporting hydrophilic molecules across the blood brain barrier remains an equally challenging problem. Hence, there is a growing effort to develop novel molecules that can pass through biological membranes and can be used as vehicles for efficient drug delivery. During the past decade, several cell penetrating peptides (CPPs) that enable the intracellular delivery of drugs have been identified. The project focuses on the structural mechanisms, namely a) identification of antimicrobial peptides that possess cell penetrating properties b) explore relationship between sequence composition and cell penetrating ability c) role of secondary structure in determining cell penetrating ability d) effect of membrane composition on cell penetrating ability of peptides during the translation of CPPs across various membrane bilayers.
Screening pesticides, toxins to identify PXR agonists and antagonists: Nuclear hormone receptors like Pregnane xenobiotic receptor (PXR) regulate the transcription of genes involved in xenobiotic metabolism and excretion. PXR agonists include a wide range of structurally diverse endogenous and exogenous compounds such as bile acids, steroid hormones, dietary fat-soluble vitamins, prescription medications, and herbal drugs, as well as environmental chemicals such as pesticides, estrogens and antiestrogens. PXR agonists can mediate clinically significant drug-drug interactions and potentiate the toxic effects of environmental chemicals. Thus PXR agonists can impact various pathophysiological states including cholesterol metabolism and endocrine modulation. We are developing novel algorithms to identify PXR agonists present in the environment and among commonly used chemicals.
Selected publications:
Troubleshooting computational methods in drug discovery.
Kortagere S., and S. Ekins.
Journal of Pharmacological and Toxicological Methods, 61(2): 67-75, 2010.
"Challenges predicting ligand-receptor interactions of promiscuous proteins: the nuclear receptor PXR."
Ekins S., Kortagere S., Iyer M., Reschly E. J., Lill M.A., Redinbo M.R., and M.D. Krasowski.
PLoS Computational Biology:., 5(12) Epub, 2009.
"Development of tolerance in D3 dopamine receptor signaling is accompanied by distinct changes in receptor conformation."
Westrich L., Gil-Mast S., Kortagere S., and E. V. Kuzhikandathil.
Biochemical Pharmacology., 79(6): 897-907, 2010.
Quaternary Benzyltriethylammonium Ion Binding to the Na,K-ATPase: a Tool to Investigate Extracellular K+ Binding Reactions.
Peluffo R.D., González-Lebrero R.M., Kaufman S.B., Kortagere S., Orban B., Rossi R.C., and J.R. Berlin. Biochemistry, 48(34):8105-19, 2009.
"Structure-activity relations of nanolipoblockers with the atherogenic domain of human macrophage scavenger receptor A."
Plourde N.M., Kortagere S., Welsh W., and P.V. Moghe.
Biomacromolecules, 10(6): 1381-1391, 2009.
"The importance of discerning shape in molecular pharmacology."
Kortagere S., Krasowski M. D., and S. Ekins.
Trends in Pharmacological Sciences., 30(3): 138-147, 2009.
"Hybrid scoring and classification approaches to predict human pregnane X receptor activators."
Kortagere S., Chekmarev D., Welsh W.J., and S. Ekins
Pharmaceutical Research, 26(4): 1001-1011, 2009.
"New Predictive Models for Blood-Brain Barrier Permeability of Drug-like Molecules."
Kortagere S., Chekmarev D., Welsh W.J., and S. Ekins.
Pharmaceutical Research., 25(8): 1836-1845, 2008.
"Halogenated Ligands and Their Interactions with Amino Acids: Implications for Structure-Activity and Structure-Toxicity Relationships."
Kortagere S., Ekins S., and W.J. Welsh.
Journal of Molecular Graphics and Modelling., 27(2): 170-177, 2008.
“Structure activity relationships” XPharm, Eds. S. J. Enna and David B. Bylund,
Kortagere, S. and J. A. Schetz.
Elsevier Inc. (e-book), 2007.
"Development and application of hybrid structure based method for efficient screening of ligands binding to G-protein coupled receptors."
Kortagere, S., and W. J. Welsh.
Journal of Computer-Aided Molecular Design., 20(12): 789-802, 2006.
" Ab initio computational modeling of long loops in G-protein coupled receptors."
Kortagere S., Roy A., and E.L. Mehler.
ournal of Computer-Aided Molecular Design, 20(7-8): 427-436, 2006.
"Ab initio computational modeling of loops in G-protein-coupled receptors: lessons from the crystal structure of rhodopsin."
Mehler E.L., Hassan S. A., Kortagere S., and H. Weinstein.
Proteins, 64(3): 673-690, 2006.
"Reciprocal Mutations in TM2/TM3 in a D2 Dopamine Receptor Background Confirms The Importance Of This Microdomain As A Selective Determinant Of Para-Halogenated 1,4-Disubstituted Aromatic Piperazines."
Floresca C. Z., Chen S., Kortagere S, and J.A Schetz.
Arch Pharmalabs (Weinheim), 338(5-6): 268-275, 2005.
"Certain 1,4-disubstituted aromatic piperidines and piperazines with extreme selectivity for the dopamine D4 receptor interact with a common receptor microdomain."
Kortagere S., Gmeiner P., Weinstein H., and J.A. Schetz.
Molecular Pharmacology., 66(6): 1491-1499, 2004.
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