title: Packing defects as selectivity switches for drug-based protein inhibitors.
abstract: The conservation of structure across homolog proteins often diffuses the impact of drug-based inhibition by promoting alternative protein-ligand associations that may lead to toxic side effects. However, sticky packing defects are typically not conserved across homologs, making them valuable a priori targets to enhance specificity. By introducing a homology to quantify packing differences among proteins, we enable a previously undescribed strategy for the design of highly selective drug inhibitors involving ligands that wrap nonconserved packing defects. The selectivity of these ligands is validated by performing affinity assays on a cancer-related pharmacokinome. Minor reengineering of a powerful inhibitor guided by wrapping differences across its target kinome can selectively direct its impact toward a specific kinase. Thus, nonconserved packing defects may be used as selectivity switches across homolog targets, using spatial displacements of packing defects across aligned protein structures.
authors.affiliation: Department of Bioengineering, Rice University, Houston, TX 77005, USA. arifer@rice.edu
authors.forename: Ariel
authors.initials: A
authors.lastname: Fernández
authors.forename: Ridgway
authors.initials: R
authors.lastname: Scott
authors.forename: R Stephen
authors.initials: RS
authors.lastname: Berry
mesh_terms: D015195:Drug Design; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D012680:Sensitivity and Specificity
chemical_list: D011506:Proteins