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Incomplete protein packing as a selectivity filter in drug design.

ABSTRACT: 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.

SUBMITTER: Fernandez A

PROVIDER: S-EPMC1963458 | biostudies-literature | 2005 Dec

REPOSITORIES: biostudies-literature

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Incomplete protein packing as a selectivity filter in drug design.

Fernández Ariel A

Structure (London, England : 1993) 20051201 12

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 ...[more]

PMID: 16338411

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