Structure-based design of potent glycogen phosphorylase inhibitors

doi:10.1017/CBO9780511730412.019

17 - Structure-based design of potent glycogen phosphorylase inhibitors

from PART III - APPLICATIONS TO DRUG DISCOVERY

Published online by Cambridge University Press: 06 July 2010

Qiaolin Deng

Edited by

Kenneth M. Merz, Jr ,

Dagmar Ringe and

Charles H. Reynolds

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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

Diabetes is a disorder of metabolism and is widely recognized as one of the leading causes of death and disability. It is estimated that more than 180 million people worldwide have diabetes. In the United States, more than 20 million people – about 7.0% of the population – have diabetes. Diabetes is a lifelong condition that, if left untreated, can lead to serious complications such as nerve damage, kidney failure, blindness, and cardiovascular diseases. Type 2 diabetes is a chronic metabolic disorder characterized by fed and fasting hyperglycemia. Glycogen phosphorylase (GP) is a key enzyme in the regulation of glycogen metabolism by catalyzing the breakdown of glycogen to glucose-1-phosphate. In muscle, glucose 1-phosphate is used to generate metabolic energy, whereas in liver it is also converted to glucose for export to peripheral tissues. There are three human isozymes of GP: liver, muscle, and brain, named to denote the tissues in which they are preferentially expressed. The muscle and brain isozymes serve the tissues in which they are found, whereas the liver isozyme meets the glycemic demands of the body as a whole. Previous reports have indicated that GP inhibition can lower blood glucose in diabetic models, thus validating it as a potential therapeutic target for treatment of type 2 diabetes. The liver isozyme of human glycogen phosphorylase (HLGP) is considered to be the preferred target for therapeutic intervention with GP inhibitors because inhibition of muscle or brain GP could lead to undesirable side effects.

Type: Chapter
Information: Drug Design
Structure- and Ligand-Based Approaches
, pp. 257 - 264

DOI: https://doi.org/10.1017/CBO9780511730412.019 [Opens in a new window]

Publisher: Cambridge University Press

Print publication year: 2010

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