Structure based identification of novel inhibitors against ATP synthase of Mycobacterium tuberculosis: A combined in silico and in vitro study
Date
2019Author
Cloete, Ruben
Grobbelaar, Melanie
Sampson, Samantha
Christoffels, Alan
Metadata
Show full item recordAbstract
The shortcomings of conventional tuberculosis treatments resulting from the development of drug resistance in
Mycobacteriumtuberculosis drive a need for the formulation of novel therapeutic agents. The diarylquinoline class
of drugs such as bedaquiline was recently approved for the treatment of multidrug-resistant strains of tuberculosis,
primarily targeting c and ε subunits of the ATP synthases. Yet resistance to bedaquiline has already been reported.
Therefore, Rv1311 was used as the target for the identification of possible inhibitors against the
M. tuberculosis. The structure of Rv1311 was predicted and common feature pharmacophore models were generated
which facilitated the identification of potential inhibitors in the ZINC database. The activities of the selected
molecules were compared with known inhibitors of the ATP synthase using quantitative structure–
activity relationship. The ZINC classified inhibitors showed comparable predicted activities with that of known
inhibitors. Furthermore, the inhibitory behavior of the studied drug molecules was experimentally determined
using in vitro techniques and showed the minimum inhibitory concentration as low as 25 μM. The resulted outcomes
provide a deeper insight into the structural basis of Rv1311 inhibitions and can facilitate the process of
drug design against tuberculosis.