Samy Meroueh, Ph.D.


Associate Professor

Department of Biochemistry and Molecular Biology
Indiana University School of Medicine
Van Nuys Medical Science Building
635 Barnhill Drive, MS 4021
Indianapolis, Indiana 46202-5126
Phone: (317) 274-8315
Facsimile: (317) 274-4686




Ph.D., 2001, Wayne State University
Post Doctoral, 2001-2003, Wayne State University
Post Doctoral, 2003-2006, University of Notre Dame


Area of Study

Chemical biology and drug discovery targeting protein-protein interactions. More details...


Selected Recent Publications

1.   Zhou, D., Bolu, L., Han, X., Xu, D., Brown, P. D., and Meroueh, S. O. (2016) Small Molecules Inhibit MELK and other Kinases to Suppress Autophagy and Growth in Basal-Like Breast Cancer Cells. Submitted

2.   Liu, D., Xu, D., Liu, M., Knabe, E. W., Yuan, C., Huang, M., and Meroueh, S. O. (2016) Small Molecules Engage Hot Spots Through Cooperative Binding to Inhibit a Tight Protein-Protein Interaction. Submitted

3.   Xu, D., Li, L., Liu, D., Knabe, E. W., Hudmon, A., and Meroueh, S. O. (2016) Structure-Based Target-Specific Screening Leads to Selective Small-Molecule CaMKIId Inhibitors Submitted

4.   Xu, D., Jalal, S., Sledge, G. W., and Meroueh, S. O. (2016) Small-Molecule Binding Sites to Explore New Protein-Protein Interactions in the Cancer Proteome. In press

5.   Xu, D., and Meroueh, S. O. (2016) Effect of Binding Pose and Modeled Structures on Enrichment of Chemical Libraries. In press

6.   Xu, D., Wang, B., and Meroueh, S. O. (2015) Structure-based computational approaches for small-molecule modulation of protein-protein interactions. Methods Mol. Biol. 1278, 77-92

7.   Liu, D., Zhou, D., Wang, B., Knabe, W. E., and Meroueh, S. O. (2015) A New Class of Orthosteric uPAR.uPA Small-Molecule Antagonists Are Allosteric Inhibitors of the uPAR.Vitronectin Interaction. ACS Chem. Biol. 10, 1521-1534

8.   Yan, C., Liu, D., Li, L., Wempe, M. F., Guin, S., Khanna, M., Meier, J., Hoffman, B., Owens, C., Wysoczynski, C. L., Nitz, M. D., Knabe, W. E., Ahmed, M., Brautigan, D. L., Paschal, B. M., Schwartz, M. A., Jones, D. N., Ross, D., Meroueh, S. O., and Theodorescu, D. (2014) Discovery and characterization of small molecules that target the GTPase Ral. Nature 515, 443-447

9.   Wang, B., Buchman, C. D., Li, L., Hurley, T. D., and Meroueh, S. O. (2014) Enrichment of chemical libraries docked to protein conformational ensembles and application to aldehyde dehydrogenase 2. J. Chem. Inf. Model. 54, 2105-2116

10.  Peng, X., Wang, F., Li, L., Bum-Erdene, K., Xu, D., Wang, B., Sinn, A. A., Pollok, K. E., Sandusky, G. E., Li, L., Turchi, J. J., Jalal, S. I., and Meroueh, S. O. (2014) Exploring a structural protein-drug interactome for new therapeutics in lung cancer. Mol. Biosyst. 10, 581-591

11.  Wang, B., Li, L., Hurley, T. D., and Meroueh, S. O. (2013) Molecular recognition in a diverse set of protein-ligand interactions studied with molecular dynamics simulations and end-point free energy calculations. J. Chem. Inf. Model. 53, 2659-2670

12.  Mani, T., Wang, F., Knabe, W. E., Sinn, A. L., Khanna, M., Jo, I., Sandusky, G. E., Sledge, G. W., Jr., Jones, D. R., Khanna, R., Pollok, K. E., and Meroueh, S. O. (2013) Small-molecule inhibition of the uPAR.uPA interaction: synthesis, biochemical, cellular, in vivo pharmacokinetics and efficacy studies in breast cancer metastasis. Biorg. Med. Chem. 21, 2145-2155

13.  Mani, T., Liu, D., Zhou, D., Li, L., Knabe, W. E., Wang, F., Oh, K., and Meroueh, S. O. (2013) Probing binding and cellular activity of pyrrolidinone and piperidinone small molecules targeting the urokinase receptor. ChemMedChem 8, 1963-1977

14.  Zhang, Q., Zeng, S. X., Zhang, Y., Zhang, Y., Ding, D., Ye, Q., Meroueh, S. O., and Lu, H. (2012) A small molecule Inauhzin inhibits SIRT1 activity and suppresses tumour growth through activation of p53. EMBO Mol. Med. 4, 298-312

15.  Wang, F., Eric Knabe, W., Li, L., Jo, I., Mani, T., Roehm, H., Oh, K., Li, J., Khanna, M., and Meroueh, S. O. (2012) Design, synthesis, biochemical studies, cellular characterization, and structure-based computational studies of small molecules targeting the urokinase receptor. Biorg. Med. Chem. 20, 4760-4773

16.  Piekarz, A. D., Due, M. R., Khanna, M., Wang, B., Ripsch, M. S., Wang, R., Meroueh, S. O., Vasko, M. R., White, F. A., and Khanna, R. (2012) CRMP-2 peptide mediated decrease of high and low voltage-activated calcium channels, attenuation of nociceptor excitability, and anti-nociception in a model of AIDS therapy-induced painful peripheral neuropathy. Mol. Pain 8, 54

17.  Wang, F., Li, J., Sinn, A. L., Knabe, W. E., Khanna, M., Jo, I., Silver, J. M., Oh, K., Li, L., Sandusky, G. E., Sledge, G. W., Nakshatri, H., Jones, D. R., Pollok, K. E., and Meroueh, S. O. (2011) Virtual screening targeting the urokinase receptor, biochemical and cell-based studies, synthesis, pharmacokinetic characterization, and effect on breast tumor metastasis. J. Med. Chem. 54, 7193-7205

18.  Shi, Q., Meroueh, S. O., Fisher, J. F., and Mobashery, S. (2011) A computational evaluation of the mechanism of penicillin-binding protein-catalyzed cross-linking of the bacterial cell wall. J Am Chem Soc 133, 5274-5283

19.  Parajuli, B., Kimble-Hill, A. C., Khanna, M., Ivanova, Y., Meroueh, S., and Hurley, T. D. (2011) Discovery of novel regulators of aldehyde dehydrogenase isoenzymes. Chem. Biol. Interact. 191, 153-158

20.  Li, L., Wang, B., and Meroueh, S. O. (2011) Support vector regression scoring of receptor-ligand complexes for rank-ordering and virtual screening of chemical libraries. J. Chem. Inf. Model. 51, 2132-2138

21.  Li, L., Khanna, M., Jo, I., Wang, F., Ashpole, N. M., Hudmon, A., and Meroueh, S. O. (2011) Target-specific support vector machine scoring in structure-based virtual screening: computational validation, in vitro testing in kinases, and effects on lung cancer cell proliferation. J. Chem. Inf. Model. 51, 755-759

22.  Khanna, M., Wang, F., Jo, I., Knabe, W. E., Wilson, S. M., Li, L., Bum-Erdene, K., Li, J., G, W. S., Khanna, R., and Meroueh, S. O. (2011) Targeting multiple conformations leads to small molecule inhibitors of the uPAR.uPA protein-protein interaction that block cancer cell invasion. ACS Chem. Biol. 6, 1232-1243

23.  Khanna, M., Chelladurai, B., Gavini, A., Li, L., Shao, M., Courtney, D., Turchi, J. J., Matei, D., and Meroueh, S. (2011) Targeting ovarian tumor cell adhesion mediated by tissue transglutaminase. Mol. Cancer Ther. 10, 626-636

24.  Brittain, J. M., Duarte, D. B., Wilson, S. M., Zhu, W., Ballard, C., Johnson, P. L., Liu, N., Xiong, W., Ripsch, M. S., Wang, Y., Fehrenbacher, J. C., Fitz, S. D., Khanna, M., Park, C. K., Schmutzler, B. S., Cheon, B. M., Due, M. R., Brustovetsky, T., Ashpole, N. M., Hudmon, A., Meroueh, S. O., Hingtgen, C. M., Brustovetsky, N., Ji, R. R., Hurley, J. H., Jin, X., Shekhar, A., Xu, X. M., Oxford, G. S., Vasko, M. R., White, F. A., and Khanna, R. (2011) Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca(2)(+) channel complex. Nat. Med. 17, 822-829

25.  Wang, Y., Brittain, J. M., Jarecki, B. W., Park, K. D., Wilson, S. M., Wang, B., Hale, R., Meroueh, S. O., Cummins, T. R., and Khanna, R. (2010) In silico docking and electrophysiological characterization of lacosamide binding sites on collapsin response mediator protein-2 identifies a pocket important in modulating sodium channel slow inactivation. J. Biol. Chem. 285, 25296-25307

26.  Li, L., Li, J., Khanna, M., Jo, I., Baird, J. P., and Meroueh, S. O. (2010) Docking Small Molecules to Predicted Off-Targets of the Cancer Drug Erlotinib Leads to Inhibitors of Lung Cancer Cell Proliferation with Suitable In vitro Pharmacokinetic Properties. ACS Med. Chem. Lett. 1, 229-233

27.  Li, L., Bum-Erdene, K., Baenziger, P. H., Rosen, J. J., Hemmert, J. R., Nellis, J. A., Pierce, M. E., and Meroueh, S. O. (2010) BioDrugScreen: a computational drug design resource for ranking molecules docked to the human proteome. Nucleic Acids Res. 38, D765-773

28.  Xue, B., Li, L., Meroueh, S. O., Uversky, V. N., and Dunker, A. K. (2009) Analysis of structured and intrinsically disordered regions of transmembrane proteins. Mol. Biosyst. 5, 1688-1702

29.  Matute, J. D., Arias, A. A., Wright, N. A., Wrobel, I., Waterhouse, C. C., Li, X. J., Marchal, C. C., Stull, N. D., Lewis, D. B., Steele, M., Kellner, J. D., Yu, W., Meroueh, S. O., Nauseef, W. M., and Dinauer, M. C. (2009) A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity. Blood 114, 3309-3315

30.  Liang, S., Meroueh, S. O., Wang, G., Qiu, C., and Zhou, Y. (2009) Consensus scoring for enriching near-native structures from protein-protein docking decoys. Proteins 75, 397-403

31.  Liang, S., Li, L., Hsu, W. L., Pilcher, M. N., Uversky, V., Zhou, Y., Dunker, A. K., and Meroueh, S. O. (2009) Exploring the molecular design of protein interaction sites with molecular dynamics simulations and free energy calculations. Biochemistry 48, 399-414

32.  Li, L., Liang, S., Pilcher, M. M., and Meroueh, S. O. (2009) Incorporating receptor flexibility in the molecular design of protein interfaces. Protein Eng. Des. Sel. 22, 575-586

33.  Shi, Q., Meroueh, S. O., Fisher, J. F., and Mobashery, S. (2008) Investigation of the mechanism of the cell wall DD-carboxypeptidase reaction of penicillin-binding protein 5 of Escherichia coli by quantum mechanics/molecular mechanics calculations. J Am Chem Soc 130, 9293-9303

34.  Li, L., and Meroueh, S. O. (2008) Receptor-Ligand Interactions in Biological Systems. in Encyclopedia for the Life Sciences, John Wiley and Sons, London. pp p. 19

35.  Li, L., Dantzer, J. J., Nowacki, J., O'Callaghan, B. J., and Meroueh, S. O. (2008) PDBcal: a comprehensive dataset for receptor-ligand interactions with three-dimensional structures and binding thermodynamics from isothermal titration calorimetry. Chem Biol Drug Des 71, 529-532

36.  Jewell, J. L., Oh, E., Bennett, S. M., Meroueh, S. O., and Thurmond, D. C. (2008) The tyrosine phosphorylation of Munc18c induces a switch in binding specificity from syntaxin 4 to Doc2beta. J. Biol. Chem. 283, 21734-21746

37.  Zhang, W., Shi, Q., Meroueh, S. O., Vakulenko, S. B., and Mobashery, S. (2007) Catalytic mechanism of penicillin-binding protein 5 of Escherichia coli. Biochemistry 46, 10113-10121

38.  Rosenblum, G., Meroueh, S., Toth, M., Fisher, J. F., Fridman, R., Mobashery, S., and Sagi, I. (2007) Molecular structures and dynamics of the stepwise activation mechanism of a matrix metalloproteinase zymogen: challenging the cysteine switch dogma. J Am Chem Soc 129, 13566-13574

39.  Meroueh, S. O., and Mobashery, S. (2007) Conformational transition in the aminoacyl t-RNA site of the bacterial ribosome both in the presence and absence of an aminoglycoside antibiotic. Chem. Biol. Drug Des. 69, 291-297

40.  Meroueh, S. O., Cha, J. Y., and Mobashery, S. (2007) Inhibition of Class A beta-Lactamases. in Enzyme-Mediated Resistance to Antibiotics: Mechanisms, Dissemination, and Prospects for Inhibition (Bonomo, R. A. ed.), ASM Press, Washington D. C. pp

41.  Li, L., Uversky, V. N., Dunker, A. K., and Meroueh, S. O. (2007) A computational investigation of allostery in the catabolite activator protein. J Am Chem Soc 129, 15668-15676

42.  Rekharsky, M., Hesek, D., Lee, M., Meroueh, S. O., Inoue, Y., and Mobashery, S. (2006) Thermodynamics of interactions of vancomycin and synthetic surrogates of bacterial cell wall. J Am Chem Soc 128, 7736-7737

43.  Rahaman, A., Song, H., Wang, A. X., Meroueh, S. O., and Hase, W. L. (2006) Chemical Dynamics Simulations of Energy Transfer and Unimolecular Decomposition in Collision-Induced Dissociation (CID) and Surface-Induced Dissociation (SID). in Principles of Mass Spectrometry Applied to Biomolecules (Litschitz, C., and Laskin, J. eds.), Wiley, New York. pp 379-432

44.  Murray, J. B., Meroueh, S. O., Russell, R. J., Lentzen, G., Haddad, J., and Mobashery, S. (2006) Interactions of designer antibiotics and the bacterial ribosomal aminoacyl-tRNA site. Chem. Biol. 13, 129-138

45.  Meroueh, S. O., Bencze, K. Z., Hesek, D., Lee, M., Fisher, J. F., Stemmler, T. L., and Mobashery, S. (2006) Three-dimensional structure of the bacterial cell wall peptidoglycan. Proc. Natl. Acad. Sci. U. S. A. 103, 4404-4409

46.  Hesek, D., Toth, M., Meroueh, S. O., Brown, S., Zhao, H., Sakr, W., Fridman, R., and Mobashery, S. (2006) Design and characterization of a metalloproteinase inhibitor-tethered resin for the detection of active MMPs in biological samples. Chem. Biol. 13, 379-386

47.  Toth, M., Osenkowski, P., Hesek, D., Brown, S., Meroueh, S., Sakr, W., Mobashery, S., and Fridman, R. (2005) Cleavage at the stem region releases an active ectodomain of the membrane type 1 matrix metalloproteinase. Biochem. J 387, 497-506

48.  Osenkowski, P., Meroueh, S. O., Pavel, D., Mobashery, S., and Fridman, R. (2005) Mutational and structural analyses of the hinge region of membrane type 1-matrix metalloproteinase and enzyme processing. J. Biol. Chem. 280, 26160-26168

49.  Meroueh, S. O., Fisher, J. F., Schlegel, H. B., and Mobashery, S. (2005) 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 127, 15397-15407

50.  Li, J., Cross, J. B., Vreven, T., Meroueh, S. O., Mobashery, S., and Schlegel, H. B. (2005) Lysine carboxylation in proteins: OXA-10 beta-lactamase. Proteins 61, 246-257

51.  Lee, M., Bernardo, M. M., Meroueh, S. O., Brown, S., Fridman, R., and Mobashery, S. (2005) Synthesis of chiral 2-(4-phenoxyphenylsulfonylmethyl)thiiranes as selective gelatinase inhibitors. Org. Lett. 7, 4463-4465

52.  Ikejiri, M., Bernardo, M. M., Meroueh, S. O., Brown, S., Chang, M., Fridman, R., and Mobashery, S. (2005) Design, synthesis, and evaluation of a mechanism-based inhibitor for gelatinase A. J. Org. Chem. 70, 5709-5712

53.  Fisher, J. F., Meroueh, S. O., and Mobashery, S. (2005) Bacterial resistance to beta-lactam antibiotics: compelling opportunism, compelling opportunity. Chem. Rev. 105, 395-424

54.  Cross, J. B., Vreven, T., Meroueh, S. O., Mobashery, S., and Schlegel, H. B. (2005) Computational investigation of irreversible inactivation of the zinc-dependent protease carboxypeptidase A. J. Phys. Chem. B 109, 4761-4769

55.  Lim, I. T., Meroueh, S. O., Lee, M., Heeg, M. J., and Mobashery, S. (2004) Strategy in inhibition of cathepsin B, a target in tumor invasion and metastasis. J Am Chem Soc 126, 10271-10277

56.  Kim, C., Haddad, J., Vakulenko, S. B., Meroueh, S. O., Wu, Y., Yan, H., and Mobashery, S. (2004) Fluorinated aminoglycosides and their mechanistic implication for aminoglycoside 3'-phosphotransferases from Gram-negative bacteria. Biochemistry 43, 2373-2383

57.  Golemi-Kotra, D., Meroueh, S. O., Kim, C., Vakulenko, S. B., Bulychev, A., Stemmler, A. J., Stemmler, T. L., and Mobashery, S. (2004) 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. 279, 34665-34673

58.  Brown, S., Meroueh, S. O., Fridman, R., and Mobashery, S. (2004) Quest for selectivity in inhibition of matrix metalloproteinases. Curr. Top. Med. Chem. 4, 1227-1238

59.  Birck, C., Cha, J. Y., Cross, J., Schulze-Briese, C., Meroueh, S. O., Schlegel, H. B., Mobashery, S., and Samama, J. P. (2004) X-ray crystal structure of the acylated beta-lactam sensor domain of BlaR1 from Staphylococcus aureus and the mechanism of receptor activation for signal transduction. J Am Chem Soc 126, 13945-13947

60.  Wilkinson, A. S., Bryant, P. K., Meroueh, S. O., Page, M. G., Mobashery, S., and Wharton, C. W. (2003) A dynamic structure for the acyl-enzyme species of the antibiotic aztreonam with the Citrobacter freundii beta-lactamase revealed by infrared spectroscopy and molecular dynamics simulations. Biochemistry 42, 1950-1957

61.  Wang, J., Meroueh, S. O., Wang, Y., and Hase, W. L. (2003) Efficiency of energy transfer in protonated diglycine and dialanine SID. Int. J. Mass spectrom. 230, 57-63

62.  Song, K., Meroueh, O., and Hase, W. L. (2003) Dynamics of Cr(CO)[sub 6][sup +] collisions with hydrogenated surfaces. The Journal of Chemical Physics 118, 2893

63.  Rosenblum, G., Meroueh, S. O., Kleifeld, O., Brown, S., Singson, S. P., Fridman, R., Mobashery, S., and Sagi, I. (2003) Structural basis for potent slow binding inhibition of human matrix metalloproteinase-2 (MMP-2). J. Biol. Chem. 278, 27009-27015

64.  Meroueh, S. O., Minasov, G., Lee, W., Shoichet, B. K., and Mobashery, S. (2003) Structural aspects for evolution of beta-lactamases from penicillin-binding proteins. J Am Chem Soc 125, 9612-9618

65.  Golemi-Kotra, D., Cha, J. Y., Meroueh, S. O., Vakulenko, S. B., and Mobashery, S. (2003) Resistance to beta-lactam antibiotics and its mediation by the sensor domain of the transmembrane BlaR signaling pathway in Staphylococcus aureus. J. Biol. Chem. 278, 18419-18425

66.  Fridman, R., Toth, M., Chvyrkova, I., Meroueh, S. O., and Mobashery, S. (2003) Cell surface association of matrix metalloproteinase-9 (gelatinase B). Cancer Metast. Rev. 22, 153-166

67.  Toth, M., Hernandez-Barrantes, S., Osenkowski, P., Bernardo, M. M., Gervasi, D. C., Shimura, Y., Meroueh, O., Kotra, L. P., Galvez, B. G., Arroyo, A. G., Mobashery, S., and Fridman, R. (2002) Complex pattern of membrane type 1 matrix metalloproteinase shedding. Regulation by autocatalytic cells surface inactivation of active enzyme. J. Biol. Chem. 277, 26340-26350

68.  Meroueh, S. O., Wang, Y., and Hase, W. L. (2002) Direct Dynamics Simulations of Collision- and Surface-Induced Dissociation of N-Protonated Glycine. Shattering Fragmentation†. The Journal of Physical Chemistry A 106, 9983-9992

69.  Meroueh, S. O., Roblin, P., Golemi, D., Maveyraud, L., Vakulenko, S. B., Zhang, Y., Samama, J. P., and Mobashery, S. (2002) Molecular dynamics at the root of expansion of function in the M69L inhibitor-resistant TEM beta-lactamase from Escherichia coli. J Am Chem Soc 124, 9422-9430

70.  Meroueh, O., and Hase, W. L. (2002) Dynamics of energy transfer in peptide-surface collisions. J Am Chem Soc 124, 1524-1531

71.  Maveyraud, L., Golemi-Kotra, D., Ishiwata, A., Meroueh, O., Mobashery, S., and Samama, J. P. (2002) High-resolution X-ray structure of an acyl-enzyme species for the class D OXA-10 beta-lactamase. J Am Chem Soc 124, 2461-2465

72.  Sun, L., de Sainte Claire, P., Meroueh, O., and Hase, W. L. (2001) Dynamics of Ar+CH[sub 4]/Ni{111} collision-induced desorption. The Journal of Chemical Physics 114, 535

73.  Meroueh, O., and Hase, W. L. (2001) Effect of surface stiffness on the efficiency of surface-induced dissociation. PCCP 3, 2306-2314

74.  Sawilowsky, E. F., Meroueh, O., Schlegel, H. B., and Hase, W. L. (2000) Structures, Energies, and Electrostatics for Methane Complexed with Alumina Clusters. The Journal of Physical Chemistry A 104, 4920-4927

75.  Meroueh, O., and Hase, W. L. (2000) Energy transfer pathways in the collisional activation of peptides. Int. J. Mass spectrom. 201, 233-244

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Research Interests

Research in the Meroueh laboratory is focused on the development of small molecules to modulate protein-protein interactions that promote cancer invasion and metastasis.  We also have a project developing small molecules to stimulate repair in spinal cord and traumatic brain injury.  We are interested in small molecules that block cancer cell invasion, migration and colonization in cancer metastasis, or small molecules that promote axonal regeneration for treatment of spinal cord and traumatic brain injuries.  The latter compounds may be useful for treatment of neurodegenerative diseases. The discovery of lead compounds is accomplished through structure-based computational screening of commercial or in-house combinatorial libraries.  We use biochemical and biophysical techniques to identify hit compounds and validate their activity.  The activity and the physico-chemical properties of compounds are optimized through a cycle of structure-based design, chemical synthesis, and in vitro biochemical or biological studies.  We are particularly interested in the protein-protein interaction networks of the urokinase receptor, Ras and Rho GTPases, and the TEAD family of transcription factors.  The ability of small molecules to prevent cancer cell invasion, migration, or to promote axonal regeneration is assessed in cell culture.  We also explore the mechanism of action of compounds through genomic and proteomic studies.  Animal studies are carried out through collaborations or using Core facilities at the Indiana University School of Medicine.

635 Barnhill Dr | Indianapolis, IN 46202 | Ph: (317) 274-7151 | Fax: (317) 274-4686