title: Identification of a selectivity determinant for inhibition of tumor necrosis factor-alpha converting enzyme by comparative modeling.
abstract: Inhibition of tumor necrosis factor-alpha converting enzyme (TACE) is a widespread objective in the search for disease modifying agents to combat rheumatoid arthritis and other autoimmune diseases. Until recently, most of the inhibitors in the literature have shown concomitant activity against the related matrix metalloproteinases (MMPs), producing undesired side effects. Here we describe the successful search for a TACE selectivity mechanism. We built a homology model based on the crystal structure of the related snake venom protein atrolysin. Comparison of the model with crystal structures of MMPs suggested a uniquely shaped S1' pocket that might be exploited for selectivity. A novel gamma-lactam scaffold was used to explore the activity profile of P1' sidechains, resulting in highly selective compounds consistent with this hypothesis. Transferability of the hypothesis was then demonstrated with five other distinct scaffolds.
authors.affiliation: Structural Biology and Molecular Design Group, Bristol-Myers Squibb Company, Experimental Station, Wilmington, DE 19880, USA. zeldaw@incyte.com
authors.forename: Zelda R
authors.initials: ZR
authors.lastname: Wasserman
authors.forename: James J-W
authors.initials: JJ
authors.lastname: Duan
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Voss
authors.forename: Chu Biao
authors.initials: CB
authors.lastname: Xue
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Cherney
authors.forename: David J
authors.initials: DJ
authors.lastname: Nelson
authors.forename: Karl D
authors.initials: KD
authors.lastname: Hardman
authors.forename: Carl P
authors.initials: CP
authors.lastname: Decicco
mesh_terms: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000595:Amino Acid Sequence; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry; D007769:Lactams / Q000737:chemistry; D020782:Matrix Metalloproteinases / Q000737:chemistry; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D017386:Sequence Homology, Amino Acid; D012910:Snake Venoms / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D007769:Lactams; D012910:Snake Venoms; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein