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.
- Ph.D. in Organic Chemistry, Pennsylvania State University - (State College, Pennsylvania, United States) 1981
- B.S. in Chemistry, University of Virginia - (Charlottesville, Virginia, United States) 1976
- Schramm, V. L., & Meek, T. D. (2019). Enhanced Antibiotic Discovery by PROSPECTing. BIOCHEMISTRY. 58(33), 3475-3476.
- Ma, Y., Li, L., He, S., Shang, C., Sun, Y., Liu, N., ... Shang, L. (2019). Application of Dually Activated Michael Acceptor to the Rational Design of Reversible Covalent Inhibitor for Enterovirus 71 3C Protease. JOURNAL OF MEDICINAL CHEMISTRY. 62(13), 6146-6162.
- Zhai, X., & Meek, T. D. (2018). Catalytic Mechanism of Cruzain from Trypanosoma cruzi As Determined from Solvent Kinetic Isotope Effects of Steady-State and Pre-Steady-State Kinetics. BIOCHEMISTRY. 57(22), 3176-3190.
- Holdgate, G. A., Meek, T. D., & Grimley, R. L. (2018). Mechanistic enzymology in drug discovery: a fresh perspective. Nature Reviews Drug Discovery. 17(2), 115-132.
- Pham, T. V., Murkin, A. S., Moynihan, M. M., Harris, L., Tyler, P. C., Shetty, N., ... Meek, T. D. (2017). Mechanism-based inactivator of isocitrate lyases 1 and 2 from Mycobacterium tuberculosis. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES. 114(29), 7617-7622.