Molecular mechanism of imidapril for cardiovascular protection via inhibition of MMP-9.
To investigate the inhibitory specificity of angiotensin converting enzyme (ACE) inhibitors to matrix metalloproteinase (MMP)-9, we predicted molecular interactions between an ACE inhibitor imidapril and MMP-9 active site based on recent X-ray structural analyses. Two binding modes differing in the orientation of imidapril on the active site were identified, and its hydrophobic group appeared to preferentially interact with the S1 site compared with the S1' site. Compared with the lisinopril-MMP-9 model in our previous study, imidapril was stabilized effectively on the active site with less of molecular distortions. We also measured ACE and MMP-9 inhibitory activities of imidapril and lisinopril after myocardial infarction. Imidapril had a stronger inhibitory activity against MMP-9 than lisinopril. These findings show that imidapril inhibits MMP-9 directly like lisinopril and its hydrophobic interactions with the S1 site of MMP-9 would be important for enhancing inhibitory activity.
Yamamoto
Daisuke
D
Biomedical Computation Center, Osaka Medical College, 2-7 Daigakuchou, Takatsuki, Osaka 569-8686, Japan. center@art.osaka-med.ac.jp
Takai
Shinji
S
Jin
Denan
D
Inagaki
Sachiko
S
Tanaka
Kazuhiko
K
Miyazaki
Mizuo
M
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D006224:Cricetinae; D006352:Heart Ventricles / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D048289:Imidazolidines / Q000378:metabolism / Q000494:pharmacology*; D017706:Lisinopril / Q000494:pharmacology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D008647:Mesocricetus; D008958:Models, Molecular; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*
D000806:Angiotensin-Converting Enzyme Inhibitors; D048289:Imidazolidines; D061965:Matrix Metalloproteinase Inhibitors; C065166:imidapril; D017706:Lisinopril