Synthesis of potential inhibitors in "mycolocterium tuberculosis"

Mycobacterium tuberculosis, the causative agent of tuberculosis, depends on the biosynthesis of 2-deoxythymidine-5-monophosphate (dTMP) for cellular replication. Until recently, the only known pathway for de novo synthesis of thymidylate was by thymidylate synthase ThyA. However, comparative genomics has demonstrated the existence of two major pathways for dTMP formation in Mycobacterium tuberculosis.  ThyX is a flavin-dependent thymidylate synthase, using methylenetetrahydrofolate as a one-carbon donor, whereas FAD fulfils the role as reductant. ThyX is absent in the human genome and ThyX and ThyA are structurally unrelated. Therefore, ThyX represents an excellent target for the development of new antimycobacterial compounds. Based on the X-ray structure and with the aid of molecular modeling, new potential inhibitors of ThyX will be designed and synthesized. Compounds will be evaluated as potential inhibitors of ThyX. The most promising analogues will be tested in cellular assays and animal models of tuberculosis.
 

Keywords:Tuberculosis, Inhibitors

Disciplines:Biomarker discovery and evaluation, Drug discovery and development, Medicinal products, Pharmaceutics, Pharmacognosy and phytochemistry, Pharmacology, Pharmacotherapy, Toxicology and toxinology, Other pharmaceutical sciences

Project type:PhD project