Computational Approaches to Combinatorial Pharmaceutical Chemistry

John Wendel, Wely Floriano, Barry Olafson, Nagarajan Vaidehi, and William A. Goddard

Materials and Process Simulation Center, Caltech

It is becoming increasingly clear that initiation and regulation of the most fundamental processes in living systems is mediated via the common denominator of phosphorylation. One particular class of the enzymes responsible for actively transferring a phosphate group from ATP to a protein substrate (kinases) has been shown to directly impact cell growth and differentiation. These cyclin dependent kinases (CDKÕ's, as they are called) are currently the focus of many research efforts aimed at using their abnormal levels of activity in tumorigenic cells to combat cancer in affected cells specifically. Due to the very broad role these molecules play in regulating the cell cycle, drugs which alter kinase activity or specificity have become important targets for many pharmaceutical companies and research groups.

At the MSC, we have been perfecting a methodology based on first principles molecular mechanics of docking potential ligands to binding pockets in proteins to predict the possible efficacy of such ligands on altering protein activity. Recently, our computational tools have been implemented with great success in modeling the efficacy of a series of ligands for the olfactory receptor in excellent agreement with experiment. We are currently in the process of bringing these computational tools to bear on the design of drugs aimed at the CDK receptor. Working closely with Sheng Ding and Peter Schultz at Scripps Institute, we are in the process of designing a streamlined protocol for computationally generating and filtering thousands of possible lead structures down to a few which merit follow-up using experimental means. We expect that our approach of computationally generating small molecule libraries for fast searching before invoking tedious experimental techniques will provide a major advance for streamlining drug design on a very broad base in the pharmaceutical industry.