My research interests are in Chemical Biology. Chemical Biology is a relatively new term used to describe the study of the chemistry that underlies all biological structure and processes. We use the principles, theories and tools that have been traditionally applied to small molecules and apply them to investigate biologically important systems. Consequently, we draw from diverse areas of chemistry and biology - ranging from computational chemistry to cell biology - to solve a biological problem.

The biological system that has been the core of our program is the microtubule. Microtubules occupy a central role in the life of a cell. Examine any cellular function that involves movement - division, directional migration, transport - and microtubules are likely to be found. These structures are a dynamic assemblage of several proteins. The central core of the microtubule is composed entirely of the protein tubulin, which is also the most abundant protein in the tubule. The exterior of the microtubule is decorated with proteins collectively termed microtubule-associated proteins, which are implicated in interactions between microtubules and other elements of the cell. Pure tubulin possesses the necessary structural features to assemble and disassemble in the absence of these proteins, and so much of what we know about microtubules has been learned from studying purified tubulin. Understanding the structure and dynamics of microtubules will enhance our understanding of fundamental cellular processes. Of equal importance is the therapeutic application of microtubule chemistry. Microtubules are the target for a number of clinically important drugs effective against a variety of disease states. Microtubule active drugs are especially important in cancer chemotherapy. For example, the Vinca alkaloids have been successfully used for many years to treat leukemia and related neoplasms. Taxol (aka paclitaxel), which is also an antimicrotubule drug, has been described as one of the most important new anticancer drugs of the past 20 years. Taxol quickly found its place in the chemical arsenal against cancer and is highly effective against some notoriously difficult tumors. Understanding the molecular interactions of these drugs with the microtubule receptor will spur the development of newer, more effective anticancer drugs.

Below are a few examples of research programs currently in progress in my lab.

Molecular mechanism of Taxol chemotherapy . Taxol has a complicated structure - difficult to synthesize and conformationally mobile. The next generation of Taxol-like drugs will ideally retain the structural features required for potency but possess much simpler structures. Design of such compounds will rely on a detailed understanding of the molecular interactions between Taxol and microtubules.

The relationship between tubulin structure and function. The paradox of tubulin structure is that it is highly conserved and highly diverse. The important contacts between tubulin monomers within a microtubule are highly conserved: it has long been known that tubulins from diverse phyla will coassemble into normal microtubules. Yet tubulin purified from a single source is fraught with multiple gene products and multiple posttranslational modifications, some of which confer distinct physical properties to the isoforms. It is also known that antimicrotubule drugs tend to display selective toxicity to different tissues. We are exploring whether tubulin microheterogeneity may cause, in part, the differential drug toxicity.

Molecular mechanisms of colchicine and related drugs. Colchicine is one of the oldest drugs in the pharmacopoeia. Medical use of colchicine has been almost continuous for 1400 years, and the drug is still a treatment of choice for acute gout. Colchicine acts by binding to a single site on unassembled tubulin, subsequently inhibiting tubulin polymerization. A surprising number of drugs bind to the same site as colchicine, including podophyllotoxin, nocodazole, and combretastatin, and new molecules with colchicine-site activity continue to be discovered. We are attempting to formulate a unified mechanism for the association of such chemically diverse structures with a single receptor site on the protein.

The techniques used to study this and other ligand-receptor systems are derived from a variety of disciplines, including, organic, physical, and biological chemistry. Specific examples are organic synthesis, protein purification and characterization, and spectroscopic techniques such as absorption, emission, and NMR spectroscopy.