A molecular modeling analysis of novel non-hydroxamate inhibitors of TACE

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 plausi...

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Published inBioorganic & medicinal chemistry letters Vol. 17; no. 5; pp. 1408 - 1412
Main Authors Sheppeck, James E., Tebben, Andrew, Gilmore, John L., Yang, Anle, Wasserman, Zelda R., Decicco, Carl P., Duan, James J.-W.
Format Journal Article
LanguageEnglish
Published Oxford Elsevier Ltd 01.03.2007
Elsevier
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Summary: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. 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.
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ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2006.11.082