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Thomas Meek

Meek, Thomas
Thomas Meek
Professor
Office:
ILSB 2126
Email:
Phone:
979-458-9787
Undergraduate Education
B. S., Chemistry, University of Virginia (1976)
Graduate Education
Ph.D. Organic Chemistry, Penn State University (1981)

Enzyme Mechanisms and Rational Design of Enzyme Inhibitors

Marketed drugs have been developed for representatives of all six classes of enzymes, and comprise essential therapies for the treatment of cancers, HIV/AIDS, hypercholesterolemia, and bacterial infections. The availability of known point mutations that are causative of human cancers , as well as the full genomic descriptions of many pathogens, such as parasitic protozoa and infectious bacteria, provides an emerging means to identify new or known enzymes that would constitute potential drug targets. Likewise, the availability of crystal structures of many of these enzymes or their analogues, provides a means to rationally design new inhibitors of enzyme drug targets via the use of molecular modelling and a full understanding of the chemical mechanism of the target enzymes, as an important adjuvant to inhibitor discovery via high-throughput screening.

Our laboratory will initially focus on the detailed study of the mechanisms of cysteine proteases such as cathepsin C, the isocitrate lyase of Mycobacterium tuberculosis, and human ATP-citrate lyase, by the use of pre-steady-state and steady-state kinetics, as well as by use of existing crystal structures of these enzymes, to inform the design of both covalent and other mechanism-based modes for the inactivation of these enzymes.  We will design and synthesize candidate inhibitors, and test them against these and other enzyme targets, and determine their suitability as potential drug candidates.

Recent Publications

  1. Poulin, MB, Schneck, JL, Matico, RE, McDevitt, PJ, Huddleston, MJ, Hou, W et al.. Transition state for the NSD2-catalyzed methylation of histone H3 lysine 36. Proc. Natl. Acad. Sci. U.S.A. 2016;113 (5):1197-201.
    doi: 10.1073/pnas.1521036113. PubMed PMID:26787850. PubMed Central PMC4747696.

  2. Brandt, M, Szewczuk, LM, Zhang, H, Hong, X, McCormick, PM, Lewis, TS et al.. Development of a high-throughput screen to detect inhibitors of TRPS1 sumoylation. Assay Drug Dev Technol. 2013;11 (5):308-25.
    doi: 10.1089/adt.2012.501. PubMed PMID:23772552. .

  3. Rubach, JK, Cui, G, Schneck, JL, Taylor, AN, Zhao, B, Smallwood, A et al.. The amino-acid substituents of dipeptide substrates of cathepsin C can determine the rate-limiting steps of catalysis. Biochemistry. 2012;51 (38):7551-68.
    doi: 10.1021/bi300719b. PubMed PMID:22928782. .

  4. Fan, F, Williams, HJ, Boyer, JG, Graham, TL, Zhao, H, Lehr, R et al.. On the catalytic mechanism of human ATP citrate lyase. Biochemistry. 2012;51 (25):5198-211.
    doi: 10.1021/bi300611s. PubMed PMID:22657152. .

  5. Totoritis, R, Duraiswami, C, Taylor, AN, Kerrigan, JJ, Campobasso, N, Smith, KJ et al.. Understanding the origins of time-dependent inhibition by polypeptide deformylase inhibitors. Biochemistry. 2011;50 (31):6642-54.
    doi: 10.1021/bi200655g. PubMed PMID:21711014. .

  6. Schneck, JL, Briand, J, Chen, S, Lehr, R, McDevitt, P, Zhao, B et al.. Kinetic mechanism and rate-limiting steps of focal adhesion kinase-1. Biochemistry. 2010;49 (33):7151-63.
    doi: 10.1021/bi100824v. PubMed PMID:20597513. .

  7. Schneck, JL, Villa, JP, McDevitt, P, McQueney, MS, Thrall, SH, Meek, TD et al.. Chemical mechanism of a cysteine protease, cathepsin C, as revealed by integration of both steady-state and pre-steady-state solvent kinetic isotope effects. Biochemistry. 2008;47 (33):8697-710.
    doi: 10.1021/bi8007627. PubMed PMID:18656960. .

  8. Marino, JP Jr, Fisher, PW, Hofmann, GA, Kirkpatrick, RB, Janson, CA, Johnson, RK et al.. Highly potent inhibitors of methionine aminopeptidase-2 based on a 1,2,4-triazole pharmacophore. J. Med. Chem. 2007;50 (16):3777-85.
    doi: 10.1021/jm061182w. PubMed PMID:17636946. .

  9. Copeland, RA, Pompliano, DL, Meek, TD. Drug-target residence time and its implications for lead optimization. Nat Rev Drug Discov. 2006;5 (9):730-9.
    doi: 10.1038/nrd2082. PubMed PMID:16888652. .

  10. Patel, MP, Liu, WS, West, J, Tew, D, Meek, TD, Thrall, SH et al.. Kinetic and chemical mechanisms of the fabG-encoded Streptococcus pneumoniae beta-ketoacyl-ACP reductase. Biochemistry. 2005;44 (50):16753-65.
    doi: 10.1021/bi050947j. PubMed PMID:16342966. .

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