title: 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.
authors.affiliation: Department of Bioengineering, Rice University, Houston, TX 77005, United States. alecrespo@rice.edu
authors.forename: Alejandro
authors.initials: A
authors.lastname: Crespo
authors.forename: Ariel
authors.initials: A
authors.lastname: Fernández
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D003429:Cross Reactions; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D006801:Humans; D006860:Hydrogen Bonding; D000068877:Imatinib Mesylate; D010879:Piperazines / Q000009:adverse effects / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry*; D011743:Pyrimidines / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011494:Protein Kinases