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.

Keywords::

• Thymidine Kinase Inhibitors
• Database Searching
• Structure-based Drug Design
• Thymidylate Kinase
• Herpes Simplex Virus Type 1
• Mycobacterium Tuberculosis