کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1378027 981992 2007 5 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
A molecular modeling analysis of novel non-hydroxamate inhibitors of TACE
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
A molecular modeling analysis of novel non-hydroxamate inhibitors of TACE
چکیده انگلیسی

Recently, an X-ray co-crystal structure of our hydroxamate inhibitor IK682 and TACE [Niu, X.; Umland, S.; Ingram, R.; Beyer, B. M.; Liu, Y.-H.; Sun, J.; Lundell, D.; Orth, P. Arch. Biochem. Biophys. 2006, 451, 43–50] was published that explicitly shows the orientation of the hydroxamate and the TACE-selective 4-[(2-methyl-4-quinolinyl)methoxy]phenyl P1′ group in the S1′ and S3′ sites. The preceding paper described a novel series of potent and TACE-selective hydantoins and we previously described pyrimidinetrione (barbiturate) inhibitors of TACE, both of which contain the same P1′ group as IK682. Using this TACE-selective P1′ group as an anchor, stereochemical and conformational constraints in the inhibitors, and restrictions to the active site Zn coordination geometry, we developed a highly plausible and predictive pharmacophore model that rationalizes the observed TACE activity of all three inhibitors.

We have developed a number of hydroxamate and non-hydroxamate inhibitors of TACE that possess the selective quinolinemethoxy P1′ group. Using the X-ray co-crystal structure of our hydroxamate IK682 and TACE, and a co-crystal structure of a pyrimidinetrione in MMP-8, we have developed a highly plausible pharmacophore model of how our pyrimidinetrione and hydantoin inhibitors bind to TACE.Figure optionsDownload as PowerPoint slide

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 17, Issue 5, 1 March 2007, Pages 1408–1412
نویسندگان
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