Lakshmi Kotra, Associate Professor,, Department of Chemistry and Biochemistry, UNCG

Kotra group is a multi-disciplinary group using advanced principles in computer modeling, synthetic medicinal chemistry and biochemistry principles to address biological problems of health relevance. Interests of the group lie in understanding enzyme/receptor structures, identifying underlying determinants in a disease process, and designing molecular intervention strategies. The research group’s interests are in the areas of infectious diseases, cancer, diabetes, and related areas. The research group enjoys devising unconventional means to dissect biological interactions and to design therapeutic strategies using chemistry principles. Kotra group enjoys collaborations with several investigators in Canada , United States of America , India and elsewhere, including the pharmaceutical industry.

Modulation of Protein-Protein Interactions using Novel Small Molecules

Protein-protein interactions are one of the fundamental interactions in the biology responsible for a number of intracellular and extracellular events, and are involved in many disease processes. Protein interactions, due to the complexity of the structural determinants responsible for such interactions, are one of the most difficult to understand and modulate for therapeutic purposes. Kotra group uses computer modeling tools and small molecule based approaches to design novel strategies to modulate (inhibit or stabilize) various therapeutically important protein-protein interactions. Synthetic chemistry, computer modeling and biochemical principles are used in this endeavor. The challenging aspects of this research are the synthesis of designed molecules that are custom-designed to compete with a specific protein partner.

Design of Mechanism-Based Enzyme Inhibitors

Kotra Research Group’s current research projects include structure-based design of inhibitors against orotidine monophosphate decarboxylase (ODCase), and design of protease inhibitors using the novel fluoropeptidomimetics strategy, among others. These projects have direct therapeutic applications in the areas of cancer, and infectious diseases such as malaria, SARS and other RNA viral diseases, bacterial infections, diabetes, and diabetes-related complications.

Accomplishments of Kotra Research Group

Kotra Laboratory successfully designed several biologically active compounds that have potent activities against infectious diseases and cancer. For example, one of the ODCase inhibitors is in the preclinical development stage against malaria, and various other compounds are currently undergoing medicinal chemistry optimization for applications in cancer and viral diseases. Additional accomplishments of the Kotra Research Group include the discovery of a new strategy, “fluoropeptidomimetics”, to inhibit proteases with a wide array of therapeutic applications, and structure-based design of small molecules targeting insulin receptor.

REPRESENTATIVE PUBLICATIONS

Fujihashi, M.; Bello, A. M.; Kotra, L. P.; Pai, E. F. Structural characterization of the molecular events during a slow substrate-product transition in Orotinde-5’-monophosphate decarboxylase. J. Mol. Biol. 2009, in press. (http://dx.doi.org/10.1016/j.jmb.2009.02.037).

Bello, A. M.; Konforte, D.; Poduch, E.; Furlonger, C.; Wei, L.; Liu, Y.; Lewis, M.; Pai, E. F.; Paige, C. J.; Kotra, L. P. Structure-activity relationships of orotidine-5’-monophosphate decarboxylase inhibitors as anticancer agents. J. Med. Chem. 2009, accepted. (http://dx.doi.org/10.1021/jm801224t)

Bello, A. M.; Bende, T.; Wei, L.; Wang, X.; Majchrzak-Kita, B.; Fish, E. N.; Kotra, L. P. De novo design of nonpeptidic compounds targeting the interactions between interferon-a and its cognate cell surface receptor. J. Med. Chem. 2008, 51, 2734-2743. (http://dx.doi.org/10.1021/jm701182y)

Tang, S.; Xiao, V.; Wei, L.; Whiteside, C. I.; Kotra, L. P. Protein kinase C isozymes and their selectivity towards ruboxistaurin. Proteins Struct. Function & Bioinform. 2008, 72, 447-460. (http://dx.doi.org/10.1002/prot.21942)

Fortin, S.; Labrie, P.; Moreau, E.; Wei, L.; Kotra, L. P.; C.-Gaudreault, R. A Comparative Molecular Field and Comparative Molecular Similarity Indices Analyses (CoMFA and CoMSIA) of N-Phenyl-N’-(2-chloroethyl)urea Targeting the Colchicine-Binding Site as Anticancer Agents. Bioorg. Med. Chem. 2008, 16, 1914-1926 (http://dx.doi.org/10.1016/j.bmc.2007.11.004).

Bello, A. M.; Poduch, E.; Liu, Y.; Wei, L.; Crandall, I.; Wang, X.; Dyanand, C.; Kain, K. C.; Pai, E. F.; Kotra, L. P. Structure-Activity Relationships of C6-Uridine Derivatives Targeting Plasmodia Orotidine Monophosphate decarboxylase. J. Med. Chem. 2008, 51 (3), 439–448. (http://dx.doi.org/10.1021/jm7010673)

Poduch, E.; Wei, L.; Pai, E. F.; Kotra, L. P. Structural Diversity and Plasticity Associated with Nucleotides targeting Orotidine Monophosphate Decarboxylase. J. Med. Chem. 2008, 51 (3), 432–438. (http://dx.doi.org/10.1021/jm700968x)

Meza-Avina, M. E.; Wei, L.; Buhendwa, M. G.; Poduch, E.; Bello, A. M.; Pai, E. F.; Kotra, L. P. Inhibition of Orotidine 5’-Monophosphate Decarboxylase and Its Therapeutic Potential. Mini-Rev. Med. Chem. 2008, 8(3), 239-247.

Kumaran, J.; Wei, L.; Kotra, L. P., Fish, E. N. A structural basis for interferon-a-receptor interactions. FASEB J. 2007, 21, 3288-3296.

Bello , A. M.; Bende, T.; Wei, L.; Fish, E. N.; Kotra, L. P. De novo design of nonpeptidic compounds targeting the interactions between interferon- a and its cognate cell surface receptor. J. Med. Chem.2007, accepted.

Tang, S.; Xiao, V.; Wei, L.; Whiteside, C. I.; Kotra, L. P. Protein kinase C isozymes and their selectivity towards ruboxistaurin. Proteins Struct. Function & Bioinform.2007, accepted.

Bello, A. M.; Poduch, E,; Liu, Y.; Wei, L.; Crandall, I.; Wang, X.; Dyanand, C.; Kain, K. C.; Pai, E. F.; Kotra, L. P. Structure-Activity Relationships of C6-Uridine Derivatives Targeting Plasmodia Orotidine Monophosphate decarboxylase. J. Med. Chem.2007, in press.

Poduch, E.; Wei, L.; Pai, E. F.; Kotra, L. P. Structural Diversity and Plasticity Associated with Nucleotides targeting Orotidine Monophosphate Decarboxylase. J. Med. Chem.2007, in press.

Kumaran, J.; Wei, L.; Kotra, L. P.; Fish, E. N. A structural basis for interferon- a -receptor interactions. FASEB J.2007, in press.

Bello, A. M.; Poduch, E.; Fujihashi, M.; Amani, M.; Li, Y.; Crandall, I.; Hui, R.; Lee, P. I.; Kain, K. C.; Pai, E. F.; Kotra, L. P. A potent, covalent inhibitor of orotidine 5’-monophosphate decarboxylase with antimalarial activity. J. Med. Chem.2007, 50(5), 915-921.

Wang, X.; Wei, L.; Kotra, L. P. Cyanocobalamin (vitamin B12) conjugates with enhanced solubility. Bioorg. Med. Chem.2007, 15, 1780-1787.

Labrie, P.; Maddaford, S. P.; Fortin, S.; Rakhit, S.; Kotra, L. P.; C.-Gaudreault, R. A Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) of Anthranilamide Derivatives that are Multidrug Resistance Modulators. J. Med. Chem.2006, 49(26), 7646-7660.

Poduch, E.; Bello , A. M.; Tang, S.; Fujihashi, M.; Pai, E. F.; Kotra, L. P. Design of Inhibitors of Orotidine Monophosphate Decarboxylase using Bioisosteric Replacement and Determination of Inhibition Kinetics. J. Med. Chem.2006, 49, 4937-4945.

Wang, M.;Kotra, L. P.; Hampson, D. R. Molecular homology modeling of G-protein coupled receptors. Curr. Comp.-Aided Drug Des.2006, 2, 95-103.

Oyiliagu, C.; Novalen, M.; Kotra, L. P. Fluorine containing molecules for peptidomimicry: A chemical act to modulate enzymatic activity. Mini-Rev. Org. Chem.2006, 3, 99-115. (invited review article)

Annedi, S. C.; Biabani, F.; Poduch, E.; Mannargudi, B. M.; Majumder, K.; Wei, L.; Khayat, R.; Tong, L.; Kotra, L. P. Engineering D-amino acid containing Novel Protease Inhibitors using Catalytic Site Architecture. Bioorg. Med. Chem. 2006, 14, 214-236.

Fujihashi, M.; Bello, A. M.; Poduch, E.; Wei, L.; Annedi, S. C.; Pai, E. F.;Kotra, L. P. An unprecedented twist for ODCase catalytic activity. J. Am. Chem. Soc.2005, 127, 15048-15050 (3-page communication).