Tuberculosis (TB) remains as one of the major public health concerns worldwide. A successful TB control and treatment is very challenging, due to continuing emergence of Mycobacterium tuberculosis strains resistant to known drugs. Therefore, the development of new drugs with different chemical and biological approaches is necessary to obtain more efficient anti-tubercular therapeutics. Biotin is an essential cofactor for lipid biosynthesis and gluconeogenesis in M. tuberculosis. M. tuberculosis relies on de novo biotin biosynthesis to obtain this vital cofactor since it cannot scavenge sufficient biotin from a mammalian host. In this study, comprehensive in silico methods including structure-based virtual screening, molecular docking, and molecular dynamic simulation analysis for ∼8000 marine natural products were performed against two essential enzymes involved in biotin synthesis and ligation of M. tuberculosis namely, pyridoxal 5'-phosphate-dependent transaminase (BioA) and mycobacterial biotin protein ligase (MtBPL). Two compounds; CMNPD10112 and CMNPD10113 are unveiled to bind the enzymes consistently and with high affinities. The binding pattern of compounds is further noticed in very stable binding modes as analyzed by molecular dynamics simulation and the mean RMSD of the complexes is within 4 Å. The intermolecular binding free energies validated complexes are less than -40 kcal/mol, which demonstrates strong and stable complexes formation. The identified hit compounds could be seeds for design of effective anti-mycobacterium therapeutics by inhibition of bacterial growth through blocking the biotin biosynthesis.Communicated by Ramaswamy H. Sarma.
Keywords: M. tuberculosis; Tuberculosis; molecular dynamics simulation; virtual screening.