Database Searching for Thymidine and Thymidylate Kinase Inhibitors Using Three-dimensional Structure-based Methods

Author： Manallack David T. Sanderson Mark R. Sohi Maninder Wien Frank Munier-Lehmann Helene Pitt Will R. Herdewijn Piet Balzarini Jan De Clercq Erik Haouz Ahmed Delarue Marc

Publisher： Informa Healthcare

ISSN： 1475-6366

Source： Journal of Enzyme Inhibition and Medicinal Chemistry, Vol.17, Iss.3, 2002-01, pp. : 167-174

Disclaimer: Any content in publications that violate the sovereignty, the constitution or regulations of the PRC is not accepted or approved by CNPIEC.

Previous Menu Next

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.