Mycobacterium tuberculosis (Mtb) is a causative agent of
tuberculosis (TB) disease, which has affected approximately 2 billion people worldwide. Due to the emergence of resistance towards the existing drugs, discovery of new anti-TB drugs is an important global healthcare challenge. To address this problem, there is an urgent need to identify new
drug targets in Mtb. In the present study, the subtractive genomics approach has been employed for the identification of new
drug targets against TB. Screening the Mtb
proteome using the Database of Essential Genes (DEG) and human
proteome resulted in the identification of 60 key
proteins which have no eukaryotic counterparts. Critical analysis of these
proteins using Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathways database revealed
uridine monophosphate kinase (UMPK)
enzyme as a potential
drug target for developing novel anti-TB drugs. Homology model of Mtb-UMPK was constructed for the first time on the basis of the crystal structure of E. coli-UMPK, in order to understand its structure-function relationships, and which would in turn facilitate to perform structure-based inhibitor design. Furthermore, the structural similarity search was carried out using physiological inhibitor
UTP of Mtb-UMPK to virtually screen
ZINC database. Retrieved hits were further screened by implementing several filters like ADME and toxicity followed by molecular docking. Finally, on the basis of the Glide docking score and the mode of binding, 6 putative leads were identified as inhibitors of this
enzyme which can potentially emerge as future drugs for the treatment of TB.