title: Inhibitor-based validation of a homology model of the active-site of tripeptidyl peptidase II.
abstract: A homology model of the active site region of tripeptidyl peptidase II (TPP II) was constructed based on the crystal structures of four subtilisin-like templates. The resulting model was subsequently validated by judging expectations of the model versus observed activities for a broad set of prepared TPP II inhibitors. The structure-activity relationships observed for the prepared TPP II inhibitors correlated nicely with the structural details of the TPP II active site model, supporting the validity of this model and its usefulness for structure-based drug design and pharmacophore searching experiments.
authors.affiliation: Johnson and Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium. hdwinter@prdbe.jnj.com
authors.forename: Hans
authors.initials: H
authors.lastname: De Winter
authors.forename: Henry
authors.initials: H
authors.lastname: Breslin
authors.forename: Tamara
authors.initials: T
authors.lastname: Miskowski
authors.forename: Robert
authors.initials: R
authors.lastname: Kavash
authors.forename: Marijke
authors.initials: M
authors.lastname: Somers
mesh_terms: D000595:Amino Acid Sequence; D000626:Aminopeptidases; D020134:Catalytic Domain; D003196:Computer Graphics; D003198:Computer Simulation; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D015195:Drug Design; D066298:In Vitro Techniques; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D012844:Sincalide / Q000378:metabolism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D015842:Serine Proteinase Inhibitors; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C048001:tripeptidyl-peptidase 2; D012697:Serine Endopeptidases; D012844:Sincalide