title: A molecular modeling analysis of novel non-hydroxamate inhibitors of TACE.
abstract: 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.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000, USA. jim.sheppeck@bms.com
authors.forename: James E
authors.initials: JE
authors.lastname: Sheppeck
authors.forename: Andrew
authors.initials: A
authors.lastname: Tebben
authors.forename: John L
authors.initials: JL
authors.lastname: Gilmore
authors.forename: Anle
authors.initials: A
authors.lastname: Yang
authors.forename: Zelda R
authors.initials: ZR
authors.lastname: Wasserman
authors.forename: Carl P
authors.initials: CP
authors.lastname: Decicco
authors.forename: James J-W
authors.initials: JJ
authors.lastname: Duan
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000072198:ADAM17 Protein; D001665:Binding Sites; D006801:Humans; D006827:Hydantoins / Q000737:chemistry / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology; D007769:Lactams / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry
chemical_list: D006827:Hydantoins; D006877:Hydroxamic Acids; C468787:IK 682; D007769:Lactams; D011744:Pyrimidinones; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; D015032:Zinc