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Database Searching for Thymidine and Thymidylate Kinase Inhibitors Using Three-dimensional Structure-based Methods |
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| Authors: | David T. Manallack Will R. Pitt Piet Herdewijn Jan Balzarini Erik De Clercq Mark R. Sanderson |
| Affiliation: | 1. Celltech R&2. D Ltd., Granta Park, Great Abington, Cambridge CB1 6GS, UK;3. Laboratory of Medicinal Chemistry and Laboratory of Virology and Chemotherapy, Rega Institute, Catholic University of Leuven, Leuven B-3000, Belgium;4. Randall Centre, New Hunt's House, King's College, Guy's Campus, London Bridge, London SE1 1UL, UK |
| 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. |
| Keywords: | Thymidine Kinase Inhibitors Database Searching Structure-based Drug Design Thymidylate Kinase Herpes Simplex Virus Type 1 Mycobacterium Tuberculosis |