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.
Highlights
In the past decades, protein kinases and G protein-coupled receptors have become the most significant group of drug targets for the pharmaceutical industry, with a large number of therapeutic molecules generated through protein kinase based drug optimization programs[1,2]
The class I as well as class II Polyphosphate kinase 2 (PPK2) enzymes are involved in the phosphorylation of nucleoside diphosphate and nucleoside monophosphate, whereas, the class III PPK2 enzymes catalyzes the direct synthesis of nucleoside triphosphates from the nucleoside monophosphates[6,7]
The past decades have seen a resurgence in the research of TB drug design and development, stimulated by an urgent need to curb the rise of the disease globally as well as to develop new, more effective therapies against drug-sensitive and resistant strains[9]
Summary
Protein kinases and G protein-coupled receptors have become the most significant group of drug targets for the pharmaceutical industry, with a large number of therapeutic molecules generated through protein kinase based drug optimization programs[1,2]. Polyphosphate kinase - 1 (PPK1), an inner cell membrane-bound enzyme, reversibly catalyze the conversion of terminal inorganic phosphate (Pi) of ATP into the long-chain Polyphosphates[6,7] This process involves the phosphorylation of histidine residue in the active site of PPK1, followed by the transformation of Pi into Inorganic Polyphosphate (Poly-P) by addition of ATP or back conversion to ATP by the addition of ADP6,7. The generated docked complexes were further analyzed using 100 ns Molecular Dynamics (MD) simulations in explicit solvent conditions and their conformational behaviors were analyzed, which validated the outcomes of molecular docking This combined in silico study provide significant structural insights into the inhibition of Rv2984 and may enable the identification of potential therapeutic agents against the infection of M. tuberculosis
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