Book of Abstracts: Albany 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.
Dept of Bioengineering