Challenges in design of biochemical assays for the identification of small molecules to target multiple conformations of protein kinases.
Protein kinases are under intense investigation because they play an important part in human diseases. Recent advances in structural biology and medicinal chemistry show that in addition to the adenosine triphosphate binding site, other 'druggable' pockets are formed at their surface when they adopt specific conformations. These findings open up the possibility of designing compounds with new modes of binding. The identification of these new inhibitors requires assays to be designed that allow the conformational flexibility of these enzymes to be better exploited. This review describes how biochemical assays can be adopted to explore these new drug design strategies.
Chène
Patrick
P
Druggability-Enzymology-Profiling Unit, Oncology Research, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. patrick_chene@yahoo.com
D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism
D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D011494:Protein Kinases