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

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.

Domains: Life Sciences [q-bio]; Other [q-bio.OT]

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, 2002, 17 (3), pp.167-74. ⟨10.1080/14756360290032949⟩. ⟨pasteur-00167044⟩