Matrix Metalloproteinase Inhibitors: A Structure−Activity Study
| Autor: | Daniel E. Levy, France Lapierre, Weisheng Liang, Wenqing Ye, Christopher W. Lange, Xiaoyuan Li, Damian Grobelny, Marie Casabonne, David Tyrrell, Kevin Holme, Alex Nadzan, Richard E. Galardy |
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| Rok vydání: | 1998 |
| Předmět: |
Stereochemistry
Matrix metalloproteinase inhibitor Matrix Metalloproteinase Inhibitors Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Gelatinase Protease Inhibitors Chromatography High Pressure Liquid chemistry.chemical_classification Hydroxamic acid biology Aryl Neutrophil collagenase Metalloendopeptidases Dipeptides Amino acid Kinetics Matrix Metalloproteinase 8 Enzyme Matrix Metalloproteinase 9 Models Chemical chemistry Gelatinases Enzyme inhibitor biology.protein Matrix Metalloproteinase 2 Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 41:199-223 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Modifications around the dipeptide-mimetic core of a hydroxamic acid based matrix metalloproteinase inhibitor were studied. These variations incorporated a variety of natural, unnatural, and synthetic amino acids in addition to modifications of the P1‘ and P3‘ substituents. The results of this study indicate the following structural requirements: (1) Two key hydrogen bonds must be present between the enzyme and potent substrates. (2) Potent inhibitors must possess strong zinc-binding functionalities. (3) The potential importance of the hydrophobic group at position R3 as illustrated by its ability to impart greater relative potency against stromelysin when larger hydrophobic groups are used. (4) Requirements surrounding the nature of the amino acid appear to be more restrictive for stromelysin than for neutrophil collagenase, 72 kDa gelatinase, and 92 kDa gelatinase. These requirements may involve planar fused-ring aryl systems and possibly hydrogen-bonding capabilities. |
| Databáze: | OpenAIRE |
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