Abstract

Tuberculosis is a chronic bacterial infection caused by Mycobacterium tuberculosis. The emergence of multidrug resistant tuberculosis has made the fight against tuberculosis more difficult. Bedaquiline is a very promising drug candidate for the treatment of tuberculosis. It has been reported that the MIC90 value of bedaquiline was remarkably low(0.06 mu g/mL), effectively inhibiting ATP synthase of mycobacteria. Potential drawbacks of bedaquiline include inhibition of the cardiac potassium channel with human Ether-a-go-go-Related Gene (hERG); with the concomitant risk of cardiac toxicity. Hence, developing new drugs with better activity and/or fewer side effects is required. In this study, we investigated in silico pharmacokinetics analysis and molecular docking methods into bedaquiline analogs selected having similarity with Bedaquiline to analyze their binding modes and their stability within the ATP synthase active site. The molecular docking results show that molecule 5 with a benzofuran group at the position R3 and the pyridine ring at position R2 with side chains interacts with residues of active sites in the same way as bedaquiline, with a binding energy of -7.12 kcal/mol. From this structural analysis the change of the phenyl cycle of bedaquiline by pyridine with a side chain in the C5 position, allows the improvement of the interaction with the hydrophobic pocket of the active site, with a significant reduction in inhibition of hERG channel potassium current (IC50 > 10 mu M) compared with bedaquiline (IC50 = 1.6 mu M). As well as the change of the Naphthalene unit by a heterocyclic aromatic group (Benzofuran) allows the improvement of the inhibitory activity (MIC90) against the M strain tb-H37Rv. The study opens up a new strategy for the development of drugs for treating tuberculosis.