Designing novel possible kinase inhibitor derivatives as therapeutics against Mycobacterium tuberculosis: An in...

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Computational Biology

Background:

• Rv2984, a polyphosphate kinase in Mycobacterium tuberculosis, is crucial for bacterial virulence and drug resistance.
• Inhibiting Rv2984 presents a potential strategy for developing new anti-tuberculosis drugs.

Purpose of the Study:

• To design and evaluate novel inhibitors targeting the Rv2984 enzyme.
• To assess the binding affinity and interaction efficacy of designed compounds against Rv2984.
• To compare the potential of new inhibitors against first-line tuberculosis drugs.

Main Methods:

• Computational identification and virtual screening of an 18-membered compound library against Rv2984.
• Molecular Dynamics (MD) simulations in explicit water conditions for 100 ns.
• Binding free energy calculations using Molecular Mechanics with the Poisson-Boltzmann and Surface Area (MM/PBSA) approach.

Main Results:

• Top three selected inhibitors exhibited binding free energies of -8.2 to -9 kcal/mol and inhibition constants of 255-866 nM.
• Designed molecules demonstrated superior binding affinities to Rv2984 compared to Isoniazid and Rifampicin.
• MD simulations and MM/PBSA analysis confirmed higher binding efficiencies for designed inhibitors, with interaction energies ranging from -100 to -1000 kJ/mol.

Conclusions:

• The designed compounds show significant potential as therapeutics against Mycobacterium tuberculosis.
• These novel inhibitors may offer a viable alternative for combating drug-resistant tuberculosis strains.
• This study provides a foundation for further drug development targeting Rv2984.