Bioorganic chemistry: Determination of enzyme mechanisms and transition states; synthesis of inhibitors, alternative substrates, and isotopically labeled compounds; enzyme kinetics
672 Natural Sciences Complex
Buffalo NY, 14260
Phone: (716) 645-4249
Fax: (716) 645-6963
The primary goal of research in the Murkin Laboratory is to understand the mechanisms of enzymatic processes related to disease and to develop inhibitors that may prove beneficial in drug development. The group employs two main approaches for such “rational design” of inhibitors: transition state mimicry and covalent inhibition.
Stable compounds that resemble the reaction’s transition state are often potent inhibitors. To design such compounds, the enzymatic transition-state structure is elucidated by a combination of experiment and computation. First, multiple kinetic isotope effects (KIEs) are measured, which give a quantitative description of the bonding changes the substrate undergoes as it traverses through the transition state. Then, a transition-state model is generated by matching experimental KIEs to those calculated using quantum mechanical computation. This model serves as a blueprint for the design of transition-state analogues.
An alternative rational strategy is the design of mechanism-based or targeted covalent inhibitors. In the former, the enzyme processes the inhibitor partially through its mechanism as if it were a substrate, but an important feature stops the reaction at an intermediate stage, trapping the enzyme as a covalent adduct. In the latter, a scaffold that is known to bind reversibly to the target enzyme is affixed with a carefully chosen electrophilic group that reacts with a neighboring amino acid residue only after binding tightly to the enzyme, leading to highly selective inhibition.
In the Murkin Laboratory, students gain expertise in many of the chemical, biochemical, and biophysical tools essential for pursuing careers in academia or industry. Among these methods are protein expression, enzyme kinetics, and synthesis of inhibitors and isotopically labeled compounds. Projects are directed at drug targets in infectious diseases including malaria, tuberculosis, and bacterial infections.