Novel matrix metalloproteinase inhibitors: generation of lead compounds by the in silico fragment-based approach
| Autor: | Minoru Nishizaki, Koji Ogawa, Masahiro Ikura, Hiromu Habashita, Hiroyuki Ohno, Kanji Takahashi, Tsuneyuki Sugiura, Hisao Nakai, Masaaki Toda, Shingo Yamamoto, Shingo Nakatani |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Models
Molecular Magnetic Resonance Spectroscopy Molecular model Matrix metalloproteinase inhibitor Stereochemistry In silico Clinical Biochemistry Pharmaceutical Science Peptide Matrix Metalloproteinase Inhibitors Spectrometry Mass Fast Atom Bombardment Biochemistry chemistry.chemical_compound Structure-Activity Relationship Amide Drug Discovery Protease Inhibitors Molecular Biology chemistry.chemical_classification Virtual screening Hydroxamic acid biology Chemistry Organic Chemistry Enzyme inhibitor biology.protein Molecular Medicine |
| Zdroj: | Bioorganicmedicinal chemistry. 13(14) |
| ISSN: | 0968-0896 |
| Popis: | Generation of structurally new matrix metalloproteinase inhibitors was successfully carried out using an in silico technique. In order to identify the small fragment interacting with residues in the S1′ pocket of MMP-1 through hydrogen bonds, we performed in silico screening using the LUDI program. As a result, acetyl- l -alanyl-(N-methyl)amide (Ac- l -Ala-NHMe) was selected to link with another fragment, hydroxamic acid that interacted with catalytic zinc. By this approach, the l -glutamic acid derivative 2b was discovered to be a new type of matrix metalloproteinase inhibitor. Further transformation to reduce its peptidic nature and improve activity yielded nonpeptidic lead compounds as inhibitors of MMP-1, -2, -3, and -9. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect