title: Identification of inhibitors against Mycobacterium tuberculosis thiamin phosphate synthase, an important target for the development of anti-TB drugs.
abstract: Tuberculosis (TB) continues to pose a serious challenge to human health afflicting a large number of people throughout the world. In spite of the availability of drugs for the treatment of TB, the non-compliance to 6-9 months long chemotherapeutic regimens often results in the emergence of multidrug resistant strains of Mycobacterium tuberculosis adding to the precariousness of the situation. This has necessitated the development of more effective drugs. Thiamin biosynthesis, an important metabolic pathway of M. tuberculosis, is shown to be essential for the intracellular growth of this pathogen and hence, it is believed that inhibition of this pathway would severely affect the growth of M. tuberculosis. In this study, a comparative homology model of M. tuberculosis thiamin phosphate synthase (MtTPS) was generated and employed for virtual screening of NCI diversity set II to select potential inhibitors. The best 39 compounds based on the docking results were evaluated for their potential to inhibit the MtTPS activity. Seven compounds inhibited MtTPS activity with IC(50) values ranging from 20-100 µg/ml and two of these exhibited weak inhibition of M. tuberculosis growth with MIC(99) values being 125 µg/ml and 162.5 µg/ml while one compound was identified as a very potent inhibitor of M. tuberculosis growth with an MIC(99) value of 6 µg/ml. This study establishes MtTPS as a novel drug target against M. tuberculosis leading to the identification of new lead molecules for the development of antitubercular drugs. Further optimization of these lead compounds could result in more potent therapeutic molecules against Tuberculosis.
authors.affiliation: Department of Biochemistry, University of Delhi, New Delhi, India.
authors.forename: Garima
authors.initials: G
authors.lastname: Khare
authors.forename: Ritika
authors.initials: R
authors.lastname: Kar
authors.forename: Anil K
authors.initials: AK
authors.lastname: Tyagi
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D003001:Cloning, Molecular; D004791:Enzyme Inhibitors / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D020102:Mycobacterium smegmatis / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology*; D015203:Reproducibility of Results; D040681:Structural Homology, Protein; D013816:Thermodynamics; D014584:User-Computer Interface
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D019883:Alkyl and Aryl Transferases; C435495:thiamin phosphate synthase