Bornyl (3,4,5-trihydroxy)-cinnamate - An optimized human neutrophil elastase inhibitor designed by free energy calculations
| Autor: | Korinna L. Dormann, Thomas Steinbrecher, Andrea Hrenn, Irmgard Merfort, Andreas Labahn |
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| Rok vydání: | 2008 |
| Předmět: |
Stereochemistry
Clinical Biochemistry Proteinase Inhibitory Proteins Secretory Pharmaceutical Science Biochemistry Drug Discovery Humans Molecular Biology IC50 Serine protease chemistry.chemical_classification Camphanes Molecular Structure biology Organic Chemistry Elastase Biological activity Ligand (biochemistry) Elastase inhibitor Enzyme chemistry Cinnamates Enzyme inhibitor biology.protein Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry. 16:2385-2390 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2007.11.070 |
| Popis: | Human neutrophil elastase (HNE), a serine protease, is involved in the regulation of inflammatory processes and controlled by endogenous proteinase inhibitors. Abnormally high levels of HNE can cause degradation of healthy tissues contributing to inflammatory diseases such as rheumatoid arthritis, and also psoriasis and delayed wound healing. In continuation of our research on HNE inhibitors we have used the recently developed binding mode model for a group of cinnamic acid derivative elastase inhibitors and created bornyl (3,4,5-trihydroxy)-cinnamate. This ligand exhibited improved binding affinity predicted by means of free energy calculations. An organic synthesis scheme for the ligand was developed and its inhibitory activity was tested toward the isolated enzyme. Its IC50 value was found to be three times lower than that of similar compounds, which is in line with the computational result showing the high potential of free energy calculations as a tool in drug development. |
| Databáze: | OpenAIRE |
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