Abstract
Small molecule inhibition of protein kinases in the treatment of significant diseases such as cancer, Alzheimers 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.
Keywords: pharmacophores, extracellular regulated kinases, atp binding pocket, pyrimidylimidazoles, x-ray co-crystallization, diaryl ketones
Current Topics in Medicinal Chemistry
Title: Structural Comparison of p38 Inhibitor-Protein Complexes: A Review of Recent p38 Inhibitors Having Unique Binding Interactions
Volume: 5 Issue: 10
Author(s): Stephen T. Wrobleski and Arthur M. Doweyko
Affiliation:
Keywords: pharmacophores, extracellular regulated kinases, atp binding pocket, pyrimidylimidazoles, x-ray co-crystallization, diaryl ketones
Abstract: Small molecule inhibition of protein kinases in the treatment of significant diseases such as cancer, Alzheimers 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.
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Cite this article as:
Wrobleski T. Stephen and Doweyko M. Arthur, Structural Comparison of p38 Inhibitor-Protein Complexes: A Review of Recent p38 Inhibitors Having Unique Binding Interactions, Current Topics in Medicinal Chemistry 2005; 5 (10) . https://dx.doi.org/10.2174/1568026054985894
DOI https://dx.doi.org/10.2174/1568026054985894 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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