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Database searching for thymidine and thymidylate kinase inhibitors using three-dimensional structure-based methods.

David T Manallack 1 Mark R Sanderson 2 Maninder Sohi 2 Frank Wien 2 Helene Munier-Lehmann 3 Will R Pitt 1 Piet Herdewijn 4 Jan Balzarini 4 Erik de Clercq 4 Ahmed Haouz 5 Marc Delarue 5
1 Celltech R&D Ltd.
2 Randall centre
3 CSM - Chimie Structurale des Macromolécules
4 Laboratory of Medicinal Chemistry
5 Biochimie Structurale
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.
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https://hal-pasteur.archives-ouvertes.fr/pasteur-00167044
Contributor : Hélène Munier-Lehmann <>
Submitted on : Tuesday, August 14, 2007 - 12:15:54 PM
Last modification on : Friday, June 11, 2021 - 5:14:06 PM

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David T Manallack, Mark R Sanderson, Maninder Sohi, Frank Wien, Helene Munier-Lehmann, et al.. Database searching for thymidine and thymidylate kinase inhibitors using three-dimensional structure-based methods.. Journal of Enzyme Inhibition and Medicinal Chemistry, Informa Healthcare, 2002, 17 (3), pp.167-74. ⟨10.1080/14756360290032949⟩. ⟨pasteur-00167044⟩

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