title: Novel matrix metalloproteinase inhibitors: generation of lead compounds by the in silico fragment-based approach.
abstract: 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.
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
authors.forename: Kanji
authors.initials: K
authors.lastname: Takahashi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ikura
authors.forename: Hiromu
authors.initials: H
authors.lastname: Habashita
authors.forename: Minoru
authors.initials: M
authors.lastname: Nishizaki
authors.forename: Tsuneyuki
authors.initials: T
authors.lastname: Sugiura
authors.forename: Shingo
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Shingo
authors.initials: S
authors.lastname: Nakatani
authors.forename: Koji
authors.initials: K
authors.lastname: Ogawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ohno
authors.forename: Hisao
authors.initials: H
authors.lastname: Nakai
authors.forename: Masaaki
authors.initials: M
authors.lastname: Toda
mesh_terms: D009682:Magnetic Resonance Spectroscopy; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors