Samy Meroueh
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Research
Research in my laboratory is concerned with the discovery and design of small molecules that alter cellular processes both in vitro and in vivo with the aim of identifying agents that can be used in the clinic for the treatment of disease. To that end, we specialize in the use and development of computational techniques that are implemented on large supercomputers for the discovery of lead molecules and their optimization. The discovery of leads is accomplished through the screening of libraries containing millions of compounds. We use biochemical and biophysical techniques to validate these hits against the target of interest; these include fluorescence spectroscopy, surface plasmon resonance, and isothermal titration calorimetry. The potency and the pharmacokinetic properties of lead compounds are then optimized through structure-based and computer-aided chemical synthesis both in our laboratory and through collaborative efforts. Computational tools in conjunction with data from NMR spectroscopy and crystallography are used to characterize the three dimensional structure of the compounds bound to their receptor, as well as the motion that these systems experience. These studies play an important role in guiding our lead optimization efforts as well as in enabling us to gain a deeper understanding of the fundamental processes that guide molecular recognition in biological systems. We are particularly interested in cell surface receptors that are implicated in various cancers and bacterial infection in Staphylococcus aureus. The ability of compounds to prevent cancer cell growth, invasion, metastasis, as well as their impact on various cellular pathways is assessed through various cell- based studies that are conducted in our laboratory. In vivo studies are carried out through collaborations with investigators in the IU School of Medicine.
Recent Publications
L. Li and S. O. Meroueh "Receptor-Ligand Interactions in Biological Systems" in: Encyclopedia for the Life Sciences, John Wiley & Sons, London 2008, in press.
L. Li, J. J. Dantzer, J. Nowacki, B. J. O?Callaghan and S. O. Meroueh "PDBcal: A Comprehensive Dataset for Receptor-Ligand Interactions with Three-Dimensional Structures and Binding Thermodynamics from Isothermal Titration Calorimetry" Chem. Biol. & Drug Design. 2008, in press.
L. Li, N. V. Uversky, K. A. Dunker and S. O. Meroueh "A Computational Investigation of Allostery in the Catabolite Activator Protein" J. Am. Chem. Soc. 2007, 129, 15668-15676.
G. Rosenblum, S. O. Meroueh, M. Toth, J. F. Fisher, R. Fridman, S. Mobashery and I. Sagi "Molecular Structures and Dynamics of the Stepwise Activation of a Matrix Metalloproteinase Zymogen: Challenging the Cysteine Switch Dogma" J. Am. Chem. Soc. 2007, 129, 13566-13574.
W. Zhang, Q. Shi, Q., S. O. Meroueh, S. B. Vakulenko and S. Mobashery "Catalytic Mechanism of Penicillin-Binding Protein 5 of Escherichia coli." J. Biol. Chem. 2007, 46, 10113-10121.
S. O. Meroueh, S. Mobashery "Conformational Transition in the Aminoacyl t-RNA Site of the Bacterial Robosome both in the Presence and Absence of an Aminoglycoside Antibiotic" Chemical Biology & Drug Design 2007, 69, 291-297.
S. O. Meroueh, J. Cha, S. Mobashery "Inhibition of Class A Beta- Lactamases" in: Enzyme-Mediated Resistance to Antibiotics: Mechanisms, Dissemination, and Prospects for Inhibition, R. A. Bonomo and M. E. Tolmasky, Eds.; ASM Press: Washington, D. C., 2007, pp 101-114.
S. O. Meroueh, K. Z. Bencze, D. Hesek, M. Lee, J. F. Fisher, T. L. Stemmler, S. Mobashery "Three-Dimensional Structure of the Bacterial Cell Wall Peptidoglycan" Proc. Natl. Acad. Sci. USA 2006, 103, 4404-4409.
J. B. Murray, S. O. Meroueh, R. J. Russell, G. Lentzen, J. Haddad, S. Mobashery "Interactions of Designer Antibiotics and the Bacterial Ribosomal Aminoacyl-tRNA Site" Chem. Biol. 2006, 13, 129-38.
P. Osenkowski, S. O. Meroueh, D. Pavel, S. Mobashery, R. Fridman "Mutational and Structural Analyses of the Hinge Region of Membrane Type 1-Matrix Metalloproteinase and Enzyme Processing" J. Biol. Chem. 2005, 280, 26160-26168.
S. O. Meroueh, J. F. Fisher, H. B. Schlegel, S. Mobashery "Ab initio QM/MM Study of Class A Beta-Lactamase Acylation: Dual Participation of Glu166 and Lys73 in a Concerted Base Promotion of Ser70" J. Am. Chem. Soc. 2005, 127, 15397-15407.
M. Ikejiri, M. M. Bernardo, S. O. Meroueh, S. Brown, M. Chang, R. Fridman, S. Mobashery "Design, Synthesis, and Evaluation of a Mechanism-Based Inhibitor for Gelatinase A" J. Org. Chem. 2005, 70, 5709-5712.
J. F. Fisher, S. O. Meroueh, S. Mobashery "Bacterial Resistance to Beta-Lactam Antibiotics: Compelling Opportunism, Compelling Opportunity" Chem. Rev. 2005, 105, 395-424.
J. B. Cross, T. Vreven, S. O. Meroueh, S. Mobashery, H. B. Schlegel "Computational Investigation of Irreversible Inactivation of the Zinc-Dependent Protease Carboxypeptidase A" J. Phys. Chem. B 2005, 109, 4761-4769.
I. T. Lim, S. O. Meroueh, M. Lee, M. J. Heeg, S. Mobashery "Strategy in Inhibition of Cathepsin B, A Target in Tumor Invasion and Metastasis" J. Am. Chem. Soc. 2004, 126, 10271-10277.
D. Golemi-Kotra, S. O. Meroueh, C. Kim, S. B. Vakulenko, A. Bulychev, A. J. Stemmler, T. L. Stemmler, S. Mobashery "The Importance of a Critical Protonation State and the Fate of the Catalytic Steps in Class A Beta-Lactamases and Penicillin-Binding Proteins" J. Biol. Chem. 2004, 279, 34665-34673.
S. Brown, S. O. Meroueh, R. Fridman, S. Mobashery "Quest for Selectivity in Inhibition of Matrix Metalloproteinases" Curr. Top. Med. Chem. 2004, 4, 1227-1238.
G. Rosenblum, S. O. Meroueh, O. Kleifeld, S. Brown, S. P. Singson, R. Fridman, S. Mobashery, I. Sagi "Structural Basis for Potent Slow Binding Inhibition of Human Matrix Metalloproteinase-2 (MMP-2)" J. Biol. Chem. 2003, 278, 27009-27015.
S. O. Meroueh, G. Minasov, W. Lee, B. K. Shoichet, S. Mobashery "Structural Aspects for Evolution of Beta-Lactamases from Penicillin-Binding Proteins" J. Am. Chem. Soc. 2003, 125, 9612-9618.
S. O. Meroueh, P. Roblin, D. Golemi, L. Maveyraud, S. B. Vakulenko, Y. Zhang, J. P. Samama, S. Mobashery "Molecular Dynamics at the Root of Expansion of Function in the M69L Inhibitor-Resistant TEM Beta-Lactamase from Escherichia coli" J. Am. Chem. Soc. 2002, 124, 9422-9430.
