Organic Chemistry:  Theoretical and computational chemistry, solvent effects, ionic liquids, drug design, sampling strategies

Our research program focuses upon the application and development of new computational tools that target organic and enzymatic catalyst design, alternative environmentally friendly solvent design, and drug discovery. Fundamental problems in organic and medicinal chemistry are probed, such as elucidation of enzymatic reactions, controlling enantioselectivity for chiral compounds, transition structure prediction, de novo design of high-affinity inhibitors, and origins of drug resistance. Our efforts focus on three areas:

Mechanistic Investigations and External Influences. The effect of solvent on chemical transformations is highly sensitive, typically giving noticeable improvement in rate acceleration and stereoselectivity when transferring from water to dipolar aprotic solvents. Many substitution and elimination reactions owe this acceleration to a greater charge differential stabilization of charged substrates and more charge delocalized transition structures via hydrogen bonding in protic solvents which is not possible in aprotic ones. The high catalytic efficiency of enzymes is due to in part to a similar destabilization by extraction of the reactants from water into the low-dielectric pocket of the binding site. To gain a deeper appreciation of enzymatic catalysis, it is essential to understand the properties and structure of the transition structure, by formulating a better understanding on how the immediate molecular environment affects the rate and selectivity of fundamentally important reactions.

Ionic Liquids. Room temperature ionic liquids are a novel and exciting class of solvents that have the potential to accelerate and control a vast range of reactions in an environmentally safe manner. The objective is to understand the microscopic details on how ionic liquids operate and to exploit this understanding to predict new ionic liquids that give optimal rate and stereoselectivity enhancements. A comprehensive understanding on how ionic liquids impact chemical reactivity will be used to influence a wide range of (1) difficult organic reactions, which benefit from toxic solvents coupled with high pressures and temperatures, and (2) enzymatic reactions, which require complex physiological conditions. The long-term intent of our research program is to create controllable, efficient, safe, and environmentally clean technologies that impact society and chemistry from the laboratory bench top to large-scale industrial manufacturing.

Drug Design.The goal is to develop and use computational methods to make predictions on the structure, energetics, and reactivity of biomolecular systems in order to solve biological problems in the life sciences. The system of interest, acetyl-CoA carboxylase (ACC), uses biotin to catalyze the formation of malonyl-CoA, playing a crucial role in the metabolism of fatty acids. A better understanding of the mechanism occurring in ACC is crucial in developing treatments for obesity and diabetes; a growing epidemic with approximately one-third of the U.S. population obese and another one-third overweight. The objective of our research is the prediction and validation of potent inhibitors for ACC and a detailed mechanistic investigation of its highly conserved biotin-binding pocket used for catalysis.

Selected Publications: