Abstract
The stereospecificity shown by a wide variety of inhibitors that are effective for carboxypeptidase A (CPA), a representative zinc protease is analyzed on the basis of inhibitor type. In cases of ground state analog inhibitors and transition state analog inhibitors, the stereoisomers having the stereochemistry that corresponds to stereochemistry of substrate are more potent, but in the case of irreversible inhibitors including mechanism-based inactivators the preferred inhibitory stereochemistry cannot be predicted simply from the substrate stereospecificity. The Ogston three point fit concept may be of great value in understanding the inhibitory stereochemistry of reversible competitive inhibitors. On the other hand, the stereochemistry of irreversible inhibitors may possibly be predicted on the ground of the transition state structure that plays a critical role in the inactivation pathway.
Keywords: Metalloprotease Inhibition, carboxypeptidase A (CPA), SUBSTRATE ANALOG INHIBITORS, Thermolysin Inhibitors
Mini-Reviews in Medicinal Chemistry
Title: Origin of Chiral Pharmacology Stereochemistry in Metalloprotease Inhibition
Volume: 1 Issue: 2
Author(s): D. H. Kim
Affiliation:
Keywords: Metalloprotease Inhibition, carboxypeptidase A (CPA), SUBSTRATE ANALOG INHIBITORS, Thermolysin Inhibitors
Abstract: The stereospecificity shown by a wide variety of inhibitors that are effective for carboxypeptidase A (CPA), a representative zinc protease is analyzed on the basis of inhibitor type. In cases of ground state analog inhibitors and transition state analog inhibitors, the stereoisomers having the stereochemistry that corresponds to stereochemistry of substrate are more potent, but in the case of irreversible inhibitors including mechanism-based inactivators the preferred inhibitory stereochemistry cannot be predicted simply from the substrate stereospecificity. The Ogston three point fit concept may be of great value in understanding the inhibitory stereochemistry of reversible competitive inhibitors. On the other hand, the stereochemistry of irreversible inhibitors may possibly be predicted on the ground of the transition state structure that plays a critical role in the inactivation pathway.
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Cite this article as:
Kim H. D., Origin of Chiral Pharmacology Stereochemistry in Metalloprotease Inhibition, Mini-Reviews in Medicinal Chemistry 2001; 1 (2) . https://dx.doi.org/10.2174/1389557013407016
DOI https://dx.doi.org/10.2174/1389557013407016 |
Print ISSN 1389-5575 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5607 |
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