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13 - Structure-based drug design case study: p38

from PART III - APPLICATIONS TO DRUG DISCOVERY

Published online by Cambridge University Press:  06 July 2010

By
Arthur M. Doweyko
Edited by
Kenneth M. Merz, Jr ,
Dagmar Ringe  and
Charles H. Reynolds
Kenneth M. Merz, Jr
Affiliation:
University of Florida
Dagmar Ringe
Affiliation:
Brandeis University, Massachusetts
Charles H. Reynolds
Affiliation:
Johnson & Johnson Pharmaceutical Research & Development
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Summary

INTRODUCTION

The overproduction of cytokines has been implicated in a wide variety of inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis, osteoporosis, Alzheimer's disease, and congestive heart failure. The ability of p38 mitogen-activated protein kinase (p38 MAPK) to regulate the release and activity of multiple pro-inflammatory cytokines has attracted the interest of numerous pharmaceutical companies and independent researchers during the past decade or so. Since its initial discovery in 1994 as a potential molecular target for a novel class of cytokine suppressive inhibitors (SB-203580), more than 150 patent applications from at least thirty pharmaceutical companies have been published, all claiming novel p38 inhibitors. Four distinct isoforms of p38 MAPK are known: p38α and p38β are widely expressed in eukaryotic cells, including endothelial and inflammatory cells; p38γ is found in skeletal muscle; and p38δ is predominantly found in the small intestine, kidneys, and lung tissue. Of these four isoforms, p38α has been the most studied and is believed to be the most physiologically relevant. Numerous reviews have been published that focus on both the biology and chemistry of p38 inhibitors. The focus of this chapter is an illustration of p38 inhibitor design guided by structural information obtained both from modeling and actual x-ray crystallographic data. Structure references with a “.pdb” suffix refer to those obtained from the Research Collaboratory for Structural Bioinformatics.

Type
Chapter
Information
Drug Design
Structure- and Ligand-Based Approaches
 , pp. 197 - 208
Publisher: Cambridge University Press
Print publication year: 2010

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References

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