title: Comparative study of purine and pyrimidine nucleoside analogues acting on the thymidylate kinases of Mycobacterium tuberculosis and of humans.
abstract: Thymidine monophosphate kinase (TMPK) from Mycobacterium tuberculosis (TMPKmt) is an attractive target for the design of specific inhibitors. This fact is the result of its key role in the thymidine pathway and of unique structural features in the active site observed by X-ray crystallography, especially in comparison to its human counterpart (TMPKh). Different 5-modified thymidine derivatives, as well as purine and pyrimidine analogues or C-nucleosides were tested on TMPKmt and TMPKh, and the results were rationalized by docking studies. 5-Halogenated 2'-deoxyuridines are the best inhibitors of TMPKmt found and present the highest selectivity indexes in favor of TMPKmt.
authors.affiliation: Institut Pasteur, Unité de Chimie Organique (URA CNRS 2128) 28, Rue du Dr Roux, 75724 Paris Cedex 15, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Pochet
authors.forename: Laurence
authors.initials: L
authors.lastname: Dugué
authors.forename: Gilles
authors.initials: G
authors.lastname: Labesse
authors.forename: Muriel
authors.initials: M
authors.lastname: Delepierre
authors.forename: Hélène
authors.initials: H
authors.lastname: Munier-Lehmann
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008545:Melanoma / Q000201:enzymology*; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D011684:Purine Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D011741:Pyrimidine Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000201:enzymology; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D011684:Purine Nucleosides; D011741:Pyrimidine Nucleosides; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase