Journal of Proteomics & Bioinformatics
Open Access
ISSN: 0974-276X
ISSN: 0974-276X
Mohd Shahbaaz and Alan Christoffels
University of Western Cape, South Africa
Posters & Accepted Abstracts: J Proteomics Bioinform
Inorganic polyphosphate (PolyP) plays an essential role in bacterial virulence and drug tolerance. The genome of Mycobacterium tuberculosis encodes for two polyphosphate kinases (PPK-1, Rv2984 and PPK-2, Rv3232c) and poly phosphatases (PPX-1, Rv0496 and PPX-2, Rv1026) for maintenance of intracellular Poly P levels. The mapping of metabolic pathways indicated Rv2984 as an essential drug target involved in the drug resistance of M. tuberculosis. Consequently, a library of 18 compounds was designed by altering the scaffolds of know inhibitors and were subjected to the virtual screening against Rv2984. The top three scoring inhibitors were selected which showed the free energy of binding 8.2�??9 kcal mol-1 and values of inhibition constant falls in the range of 255�??866 nM. The binding affinities of these selected molecules were compared with the first line drugs isoniazid and rifampicin. These observations indicated that the selected inhibitors showed relatively higher binding affinity against Rv2984. Furthermore, these docked complexes were further analyzed using 100 ns molecular dynamics (MD) simulations in explicit water conditions. Through the assessment of obtained trajectories, the interactions between the protein and the inhibitors were evaluated using MM/PBSA technique, which calculates the total interaction energies between -100 kJ mol-1 to -1000 kJ mol-1. This study will facilitate the process of drug designing against M. tuberculosis and the outcomes can be validated using experimental inhibition studies. In conclusion, the designed derivatives inhibit the activity of Rv2984 more efficiently and outcomes will be validated using experimental inhibition studies. Recent Publications: 1. Cloete R, Oppon E, Murungi E, Schubert W D and Christoffels A (2016) Resistance related metabolic pathways for drug target identification in Mycobacterium tuberculosis. BMC Bioinformatics 17:75. 2. Singh M, Tiwari P, Arora G, Agarwal S, Kidwai S, et al., (2016) Establishing Virulence Associated Polyphosphate Kinase 2 as a drug Mycobacterium tuberculosis. Scientific Reports 6:26900.