Mechanistic insights into the dual inhibition strategy for checking Leishmaniasis

Abstract

Leishmaniasis ¹

¹These authors contributed equally.

is an endemic disease mainly caused by the protozoan Leishmania donovani (Ld). Polyamines have been identified as essential organic compounds for the growth and survival of Ld. These are synthesized in Ld by polyamine synthesis pathway comprising of many enzymes such as ornithine decarboxylase (ODC), spermidine synthase (SS), and S-adenosylmethionine decarboxylase. Inhibition of these enzymes in Ld offers a viable prospect to check its growth and development. In the present work, we used computational approaches to search natural inhibitors against ODC and SS enzymes. We predicted three-dimensional structures of ODC and SS using comparative modeling and molecular dynamics (MD) simulations. Thousands of natural compounds were virtually screened against target proteins using high throughput approach. MD simulations were then performed to examine molecular interactions between the screened compounds and functional residues of the active sites of the enzymes. Herein, we report two natural compounds of dual inhibitory nature active against the two crucial enzymes of polyamine pathway of Ld. These dual inhibitors have the potential to evolve as lead molecules in the development of antileishmanial drugs.

Keywords:

• dual inhibition
• leishmaniasis
• leishmania donovani
• molecular modeling
• molecular dynamics
• ornithine decarboxylase
• spermidine synthase

Acknowledgements

The authors acknowledge: the Bioinformatics facility at the Distributed Information Sub Centre, Department of Biochemical Engineering and Biotechnology, IIT Delhi, and the Department of Bioinformatics at Alagappa University, Karaikudi. This work was supported by a grant from Department of Biotechnology (DBT), Government of India, New Delhi to VKD and DS.

Notes

¹These authors contributed equally.