title: Database searching for thymidine and thymidylate kinase inhibitors using three-dimensional structure-based methods.
abstract: Structure-based drug design methods were used to search for novel inhibitors of herpes simplex virus type 1 (HSV-1) thymidine kinase and Mycobacterium tuberculosis thymidylate kinase. The method involved the use of crystal structure complexes to guide database searching for potential inhibitors. A number of weak inhibitors of HSV-2 were identified, one of which was found to inhibit HSV-1 TK and HSV-1 TK-deficient viral strains. Each compound tested against M. tuberculosis thymidylate kinase was found to have some activity. The best of these compounds was only 4.6-fold less potent than 3'-azido-3'-deoxythymidine-5'-monophosphate (AZTMP). This study demonstrates the utility of structure-based drug design methods in the search for novel enzyme inhibitors.
authors.affiliation: Celltech R&D Ltd., Great Abington, Cambridge, UK. david.manallack@denovopharma.com
authors.forename: David T
authors.initials: DT
authors.lastname: Manallack
authors.forename: Will R
authors.initials: WR
authors.lastname: Pitt
authors.forename: Piet
authors.initials: P
authors.lastname: Herdewijn
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Mark R
authors.initials: MR
authors.lastname: Sanderson
authors.forename: Maninder
authors.initials: M
authors.lastname: Sohi
authors.forename: Frank
authors.initials: F
authors.lastname: Wien
authors.forename: Helene
authors.initials: H
authors.lastname: Munier-Lehmann
authors.forename: Ahmed
authors.initials: A
authors.lastname: Haouz
authors.forename: Marc
authors.initials: M
authors.lastname: Delarue
mesh_terms: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D001665:Binding Sites; D002460:Cell Line; D016208:Databases, Factual; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D018259:Herpesvirus 1, Human / Q000201:enzymology; D018258:Herpesvirus 2, Human / Q000201:enzymology; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000201:enzymology; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors*
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D004791:Enzyme Inhibitors; D013937:Thymidine Kinase; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase