Novel matrix metalloproteinase inhibitors: generation of lead compounds by the in silico fragment-based approach.
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.
Takahashi
Kanji
K
Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
Ikura
Masahiro
M
Habashita
Hiromu
H
Nishizaki
Minoru
M
Sugiura
Tsuneyuki
T
Yamamoto
Shingo
S
Nakatani
Shingo
S
Ogawa
Koji
K
Ohno
Hiroyuki
H
Nakai
Hisao
H
Toda
Masaaki
M
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
D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors