Structural comparison of p38 inhibitor-protein complexes: a review of recent p38 inhibitors having unique binding interactions.
Small molecule inhibition of protein kinases in the treatment of significant diseases such as cancer, Alzheimer's disease, diabetes, and rheumatoid arthritis has attracted significant attention over the past two decades and has clearly become one of the most significant challenges for drug discovery in the 21st century. While the recent identification of 518 different kinases in the human genome has offered a wealth of opportunities for drug intervention in the treatment of these diseases, it has also created a daunting challenge with respect to selective kinase inhibition as a viable strategy in target-based drug design. Over the past decade, the design and development of a small molecule that selectively inhibits the p38 mitogen activated protein (MAP) kinase has clearly emerged as one of these challenges within the industry. This review will focus on the comparison of the x-ray crystal structures and binding models of the most recent p38 inhibitor-enzyme complexes and the identification of the structural elements and interactions that may be important in providing inhibitor potency and selectivity toward the p38 MAP kinase.
Wrobleski
Stephen T
ST
Department of Discovery Chemistry, Bristol-Myers Squibb, P.O. Box 4000, Princeton, New Jersey 08543-4000, USA. stephen.wrobleski@bms.com
Doweyko
Arthur M
AM
D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D008956:Models, Chemical; D008958:Models, Molecular; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D001549:Benzamides; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D007211:Indoles; C030374:indole; D048051:p38 Mitogen-Activated Protein Kinases