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

Area of Science:

• Biochemistry
• Drug Discovery
• Structural Biology

Background:

• Herpes simplex virus type 1 (HSV-1) and Mycobacterium tuberculosis (M.tb) pose significant health challenges.
• Thymidine kinase (TK) and thymidylate kinase are crucial enzymes in viral and bacterial replication, respectively.
• Targeting these enzymes offers a potential strategy for developing novel therapeutics.

Purpose of the Study:

• To identify novel inhibitors of HSV-1 thymidine kinase and M.tb thymidylate kinase using structure-based drug design.
• To evaluate the efficacy of identified compounds against relevant viral and bacterial strains.
• To demonstrate the applicability of structure-based drug design in discovering enzyme inhibitors.

Main Methods:

• Utilized crystal structure complexes of target enzymes to guide database searching for potential inhibitors.
• Employed structure-based drug design principles to virtually screen compound libraries.
• Synthesized and tested identified compounds for inhibitory activity against HSV-1 TK and M.tb thymidylate kinase.

Main Results:

• Identified weak inhibitors of herpes simplex virus type 2 (HSV-2), with one compound showing activity against HSV-1 TK and HSV-1 TK-deficient strains.
• All tested compounds exhibited some level of activity against M.tb thymidylate kinase.
• The most potent M.tb thymidylate kinase inhibitor was found to be 4.6-fold less potent than 3'-azido-3'-deoxythymidine-5'-monophosphate (AZTMP).

Conclusions:

• Structure-based drug design is an effective approach for discovering novel enzyme inhibitors.
• The study identified promising lead compounds for further development against HSV-1 and M.tb infections.
• This work highlights the potential of targeting viral and bacterial kinases for therapeutic intervention.