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Kinase packing defects as drug targets.


ABSTRACT: Protein kinases constitute major targets in molecular cancer therapy. The structural conservation of kinases causes specificity problems in most drug inhibitors, often resulting in dangerous side effects. Here we survey recent approaches in drug design that exploit a molecular marker for specificity: the pattern of packing defects. These packing defects are solvent-exposed intramolecular hydrogen bonds that may be protected by drugs upon association. In this light, we review design strategies to achieve paralogue discrimination, to control cross reactivity and to overcome drug resistance induced by target mutations.

SUBMITTER: Crespo A 

PROVIDER: S-EPMC2136416 | biostudies-literature | 2007 Nov

REPOSITORIES: biostudies-literature

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Kinase packing defects as drug targets.

Crespo Alejandro A   Fernández Ariel A  

Drug discovery today 20071030 21-22


Protein kinases constitute major targets in molecular cancer therapy. The structural conservation of kinases causes specificity problems in most drug inhibitors, often resulting in dangerous side effects. Here we survey recent approaches in drug design that exploit a molecular marker for specificity: the pattern of packing defects. These packing defects are solvent-exposed intramolecular hydrogen bonds that may be protected by drugs upon association. In this light, we review design strategies to  ...[more]

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