Incomplete protein packing as a selectivity filter in drug design.
The conservation of structure across paralog proteins promotes alternative protein-ligand associations often leading to side effects in drug-based inhibition. However, sticky packing defects are typically not conserved across paralogs, making them suitable targets to reduce drug toxicity. This observation enables a strategy for the design of highly specific inhibitors involving ligands that wrap nonconserved packing defects. The selectivity of these inhibitors is evidenced in affinity assays on a cancer-related pharmacokinome: a powerful inhibitor is redesigned by using the wrapping technology to enhance its selectivity and affinity for a target kinase. In this way, the packing defects of a soluble protein may be used as selectivity filters for drug design.
Fernández
Ariel
A
Department of Bioengineering, Rice University, Houston, Texas 77005, USA. arifer@rice.edu
D000970:Antineoplastic Agents / Q000737:chemistry*; D015195:Drug Design; D008024:Ligands; D017510:Protein Folding; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*
D000970:Antineoplastic Agents; D008024:Ligands; D011506:Proteins