Designing novel possible kinase inhibitor derivatives as therapeutics against Mycobacterium tuberculosis: An in silico study
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Date
2019
Journal Title
Journal ISSN
Volume Title
Publisher
Scientific Reports
Abstract
Rv2984 is one of the polyphosphate kinases present in Mycobacterium tuberculosis involved in the
catalytic synthesis of inorganic polyphosphate, which plays an essential role in bacterial virulence
and drug resistance. Consequently, the structure of Rv2984 was investigated and an 18 membered
compound library was designed by altering the scaffolds of computationally identified inhibitors. The
virtual screening of these altered inhibitors was performed against Rv2984 and the top three scoring
inhibitors were selected, exhibiting the free energy of binding between 8.2–9 kcal mol−1 and inhibition
constants in the range of 255–866 nM. These selected molecules showed relatively higher binding
affinities against Rv2984 compared to the first line drugs Isoniazid and Rifampicin. Furthermore, the
docked complexes were further analyzed in explicit water conditions using 100 ns Molecular Dynamics
simulations. Through the assessment of obtained trajectories, the interactions between the protein
and selected inhibitors including first line drugs were evaluated using MM/PBSA technique. The
results validated the higher efficiency of the designed molecules compared to 1st line drugs with total
interaction energies observed between −100 kJ mol−1 and −1000 kJ mol−1. This study will facilitate
the process of drug designing against M. tuberculosis and can be used in the development of potential
therapeutics against drug-resistant strains of bacteria.
Description
Keywords
Kinase inhibitor, Mycobacterium tuberculosis, Inorganic polyphosphate, Bacteria, Pharmaceutical industry
Citation
Shahbaaz, M., Nkaule, A., & Christoffels, A. (2019). Designing novel possible kinase inhibitor derivatives as therapeutics against mycobacterium tuberculosis: An in silico study. Scientific Reports, 9(1) doi:10.1038/s41598-019-40621-7