In vitro and in silico analysis of L. donovani enoyl acyl carrier protein reductase - A possible drug target

Abstract

The emergence of increased resistance to the available drugs has created a situation that demands to find out more specific molecular drug targets for Leishmaniasis. The enoyl acyl carrier protein reductase (ENR), a regulatory enzyme in type II fatty acid synthesis, was confirmed as a novel drug target and triclosan as its specific inhibitor in many microorganisms. In this study, the triclosan was tested for the leishmanicidal property against Leishmania donovani (L. donovani) and the results of in vitro and ex vivo drug assays on promastigotes and amastigotes showed that triclosan possessed antileishmanial activity with a half minimal inhibitory concentration (IC₅₀) of 30 µM. Consequently, adopting in silico approach, we have tested the triclosan’s ability to bind with the L. donovani enoyl acyl carrier protein reductase (LdENR). The 3D structure of LdENR was modelled, triclosan and cofactors were docked in LdENR model and molecular dynamic simulations were performed to observe the protein-ligands interactions, stability, compactness and binding energy calculation of the ligands-LdENR complexes. The observation showed that triclosan stably interacted with LdENR in presence of both the cofactors (NADPH and NADH), however, simulation results favor NADH as a preferred co-factor for LdENR. These results support that the reduction of L. donovani growth in the in vitro and ex vivo drug assays may be due to the interaction of triclosan with LdENR, which should be confirmed through enzymatic assays. The results of this study suggest that LdENR could be a potential drug target and triclosan as a lead for Leishmaniasis.

Communicated by Ramaswamy H. Sarma

Keywords:

• Enoyl acyl carrier protein reductase (ENR)
• triclosan (TCL)
• Leishmania donovani
• drug assays
• cytotoxicity
• molecular modelling
• molecular dynamic Simulation

Acknowledgements

The student fellowship (Shalini Yadav, Reg. No. 09/993/(0004)/2016 -EMR-1) was provided by the Council of Scientific and Industrial Research CSIR, India. The author Shalini Yadav thanks Calcutta University for allowing her to perform research in RMRIMS. Authors thank ICMR-RMRIMS for all the facility provided to carry out this research. The author Vijayakumar Saravanan particularly thanks ICMR-RMRIMS for providing the computational facility.

Disclosure statement

No conflict of interests exists.

Additional information

Funding

This work is funded by ICMR-Rajendra Memorial Research Institute of Medical Sciences under intramural grant (INT-124-BAS/2016).