Image of Kortagere, Sandhya

Sandhya Kortagere, PhD

Assistant Professor

  • Department:Microbiology and Immunology
  • Education: PhD - Molecular Pharmacology, National Institute of Mental Health and Neurosciences, India (2003)
Research Overview

Dr. Kortagere is interested in designing small molecule modulators of therapeutically relevant protein targets using structure based drug design methods.

Research

Research: Our laboratory focuses on designing small molecule inhibitors, activators, modulators or probes to therapeutically relevant protein targets using the hybrid structure based (HSB) method. The HSB method is based on a rich platform of algorithms for pharmacophore design, molecular screening, homology modeling, chemical filtering and molecular docking that is customized uniquely to every target of interest. The HSB method has been successfully applied to design small molecule modulators to a number of targets as described below:

Design 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. The HSB method was applied to design small molecule inhibitors to A) MTIP-MyoA complex present in the inner membrane complex of Plasmodium falciparum B) apical membrane antigen-1 of P. falciparum that is involved in invasion of the parasite to red blood cells C) VAR2CSA protein – a member of the P. falciparum erythrocyte membrane protein-1 family responsible for pregnancy-associated malaria and D) the enzyme PfUCHL3 with dual activity as a deubiquitylase and a deneddylase.

Our research aims to design antimalarial compounds that target unique protein-protein interactions

Develop inhibitors of novel HIV-1 protein targets: Although great advances have been made in the development of effective therapeutic strategies such as the highly active antiretroviral therapy (HAART) to treat patients, the acquired immune deficiency syndrome (AIDS) epidemic continues.  Our laboratory is involved in utilizing novel protein-protein interactions as therapeutic targets. A) The HIV-1 capsid (CA) protein plays essential roles in both early and late stages of viral replication and has emerged as a novel drug target. The HSB method was used to identify small molecules with the potential to interact with the N-terminal domain of HIV-1 CA and disrupt early, preintegration steps of the HIV-1 replication cycle. The small molecule 4,4'-[dibenzo[b,d]furan-2,8-diylbis(5-phenyl-1H-imidazole-4,2-diyl)]dibenzoic acid (CK026), which had anti-HIV-1 activity in single- and multiple-round infections was identified. Further optimization led to the design of 4-(4,5-diphenyl-1H-imidazol-2-yl)benzoic acid (I-XW-053), which retained all of the antiviral activity of the parental compound and inhibited the replication of a diverse panel of primary HIV-1 isolates in PBMCs, while displaying no appreciable cytotoxicity. This antiviral activity was specific to HIV-1, as I-XW-053 displayed no effect on the replication of SIV or against a panel of non-retroviruses. B) The viral protein Tat hijacks the host cell’s RNA polymerase II elongation control machinery by coupling with positive transcription elongation factor (P-TEFb) and directs this host factor to promote productive elongation of HIV-1 mRNA. Thus, inhibiting this protein-protein interaction between P-TEFb and Tat complex would help block HIV-1 replication. We have recently screened for small molecule inhibitors that inhibit HIV-1 replication using the P-TEFb – Tat complex as a template to the HSB method.

Our lab hopes to develop inhibitors of novel HIV-1 protein targets

Design novel Dopamine D3 receptor selective agonistsDesign novel dopamine D3 receptor selective agonists: The dopamine D3 receptor has been implicated as a potential target for drug development in various complex psychiatric disorders including psychosis, drug dependence, Parkinson's disease and dyskinesias. 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. The D3 dopamine receptor exhibits tolerance and slow response termination (SRT) properties that are not exhibited by the closely-related D2 dopamine receptors. The HSB method was utilized to design novel, selective D3 agonists that did not induce SRT and tolerance. This project focuses on understanding the conformational changes induced by these unique atypical agonists upon binding to the D3 receptor that can reveal the underlying molecular mechanisms involved in L-dopa induced dyskinesias. The lead molecule is water soluble with good pharmacokinetic properties and promising efficacy in animal models of L-dopa induced dyskinesia.

Screening for allosteric modulators of monoamine transportersScreen for allosteric modulators of monoamine transporters: Monoamine transporters are an integral part of neurotransmitter homeostasis. Dysregulation of these transporters leads to neurological and psychiatric disorders. Most significant members of this family of transporters include Dopamine transporter (DAT) and serotonin transporter (SERT). Psychostimulants such as cocaine, methamphetamine and MDMA elicit their effect through either the inhibition (cocaine) or reversal (amphetamines) of transporter function DAT and SERT. In collaboration with Dr. Ole Mortensen, we have developed an alternative approach to block the effects of psychostimulants using allosteric modulation of these transporters. Using the HSB method, we have identified two compounds, K-822 and K-986, that bind to one of the allosteric sites, cause specific conformational changes, and modulate transporter interaction with psychostimulants and yet have no adverse effects on the normal transport of endogenous substrates.

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.

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) the relationship between sequence composition and cell penetrating ability, c) the role of secondary structure in determining cell penetrating ability, and d) the 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.

Publications

Selected publications:

"Inhibiting early-stage events in HIV-1 replication by small-molecule targeting of the HIV-1 capsid"
Kortagere S, Madani N, Mankowski MK, Schön A, Zentner I, Swaminathan G, Princiotto A, Anthony K, Oza A, Sierra LJ, Passic SR, Wang X, Jones DM, Stavale E, Krebs FC, Martín-García J, Freire E, Ptak RG, Sodroski J, Cocklin S, and AB Smith III
J. Virol, 86(16): 8472-8481, 2012.

"Identification and characterization of a novel class of atypical dopamine receptor agonists"
Kuzhikandathil EV, and S Kortagere
Pharm. Res, 29(8): 2264-2275, 2012.

"Rapid discovery of inhibitors of Toxoplasma gondii using hybrid structure-based computational approach"
Kortagere S, Mui E, McLeod R, and WJ Welsh
J. Comput. Aided Mol. Des, 25(5): 403-411, 2011.

"Interaction of novel hybrid compounds with the D3 dopamine receptor: Site-directed mutagenesis and homology modeling studies"
Kortagere S, Cheng SY, Antonio T, Zhen J, Reith ME, and AK Dutta
Biochem. Pharmacol, 81(1): 157-163, 2011.

"Structure-based design of novel small-molecule inhibitors of Plasmodium falciparum"
Kortagere S, Welsh WJ, Morrisey JM, Daly T, Ejigiri I, Sinnis P, Vaidya AB, and LW Bergman
J. Chem. Inf. Model, 50(5) :840-849, 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) 1000594, 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.

"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.

"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 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.

"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.

Teaching

Dr. Kortagere is an assistant professor in the Department of Microbiology & Immunology at Drexel University College of Medicine.

Research Location

Department of Microbiology & Immunology
2900 Queen Lane
Philadelphia, PA 19129
Phone: 215-991-8135
Fax: 215-848-2271

Lab location: Queen Lane Room G81

Email Dr. Kortagere

Related Pages

Microbiology & Immunology

Biomedical Graduate Studies

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