Book of Abstracts: Albany 2005

category image Volume 22
No. 6
June 2005

Packing Defects as Drug Targets: Dodging the Side Effect

The conservation of domain structure across paralog proteins poses serious problems to drug-based inhibitor design as it often leads to side effects resulting from alternative protein-ligand associations. However, sticky packing sites in protein structure, specifically under-wrapped or solvent-exposed hydrogen bonds, are typically not conserved across homologs, making them suitable targets to minimize drug toxicity. While packing defects have not been purposely targeted in current drug designs, I show them to be commonly wrapped or protected by the inhibitor in protein-inhibitor PDB complexes. This finding implies a novel strategy for inhibitor design that minimizes side effects by introducing ligands to wrap specific packing defects in the protein.

Ariel Fernandez

Dept of Bioengineering
Rice Univesity Houston TX 77005

Department of Computer Science
The University of Chicago
Chicago, IL 60637

Phone: 317 278 9219
Fax: 317 278 9217
Email: ariel@uchicago.edu