Subscribe to thousands of academic journals for just $40/month
Read and share the articles you need for your research, all in one place.

Packing defects as selectivity switches for drug-based protein inhibitors

Details

Publisher
National Acad Sciences
Copyright
Copyright ©2009 by the National Academy of Sciences
ISSN
0027-8424
eISSN
1091-6490
Publisher site
See Article on Publisher Site

Preview Only

Expand Tray Hide Tray

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.
Loading next page...

Preview Only. This article cannot be rented because we do not currently have permission from the publisher.

 
/lp/pnas/packing-defects-as-selectivity-switches-for-drug-based-protein-0MviViTOVm