title: Crystallographic study of inhibitors of tRNA-guanine transglycosylase suggests a new structure-based pharmacophore for virtual screening.
abstract: The enzyme tRNA-guanine transglycosylase (TGT) is involved in the pathogenicity of Shigellae. As the crystal structure of this protein is known, it is a putative target for the structure-based design of inhibitors. Here we report a crystallographic study of several new ligands exhibiting a 2,6-diamino-3H-quinazolin-4-one scaffold, which has been shown recently to be a promising template for TGT-inhibitors. Crystal structure analysis of these complexes has revealed an unexpected movement of the side-chain of Asp102. A detailed analysis of the water network disrupted by this rotation has lead to the derivation of a new composite pharmacophore. A virtual screening has been performed based on this pharmacophore hypothesis and several new inhibitors of micromolar binding affinity with new skeletons have been discovered.
authors.affiliation: Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35032 Marburg, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Brenk
authors.forename: Emmanuel A
authors.initials: EA
authors.lastname: Meyer
authors.forename: Klaus
authors.initials: K
authors.lastname: Reuter
authors.forename: Milton T
authors.initials: MT
authors.lastname: Stubbs
authors.forename: George A
authors.initials: GA
authors.lastname: Garcia
authors.forename: François
authors.initials: F
authors.lastname: Diederich
authors.forename: Gerhard
authors.initials: G
authors.lastname: Klebe
mesh_terms: D001224:Aspartic Acid / Q000378:metabolism; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010430:Pentosyltransferases / Q000737:chemistry* / Q000378:metabolism; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry*; D013329:Structure-Activity Relationship; D017355:Zymomonas / Q000737:chemistry / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D011799:Quinazolines; D001224:Aspartic Acid; D010430:Pentosyltransferases; C020837:queuine tRNA-ribosyltransferase