Use of free energy methods and structure-based drug design in the discovery of a potential new class of drugs for diabetes

COMP 399

M. Rami Reddy, reddy@mbasis.com, Metabasis Therapeutics Inc, 11119 North Torrey Pines Road, La Jolla, CA 92037, Mark D. Erion, Metabasis Therapeutics, Inc, 11119 North Torrey Pines Road, La Jolla, CA 92037, Qun Dang, Department of Medicinal Chemistry, Metabasis Therapeutics, Inc, 11119 North Torrey Pines Road, La Jolla, CA 92037, Paul D. van Poelje, vanpoelje@mbasis.com, Department of Biosciences, Metabasis Therapeutics, Inc, 11119 North Torrey Pines Rd, La Jolla, CA 92037, and William N. Lipscomb, Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138.
Computational assessment of the binding affinity of enzyme inhibitors prior to synthesis is an important component of computer-assisted drug design (CADD) paradigms. Potential drug molecules for diabetes were designed using CADD approaches based on fructose 1,6-bisphosphatase (FBPase) inhibitor complex X-ray crystal structures. Although free energy perturbation (FEP) methodology is the most accurate means of estimating relative binding affinities of inhibitors, practical applications are restricted to analysis of structurally related inhibitors due to its complexity and computation-intensive nature. However, FEP calculations played an important role in this project in helping to elucidate the contributions of individual heteroatoms of adenosine monophosphate to FBPase binding affinity as well as for predicting relative solvation and binding free energies of enzyme inhibitors. The interplay of crystallography, medicinal chemistry, biology and FEP methods in the structure-based drug design of clinical candidates for type-2 diabetes will be discussed.
 

Free Energy Computations in Drug Discovery
1:00 PM-6:00 PM, Thursday, 14 September 2006 Moscone Center -- Room 220/222, Oral

Division of Computers in Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006