Molecular docking study on antiparasitic nucleoside drugs

New drugs against trypanosomiasis and leishmaniasis are urgently needed, including for veterinary applications, and any new drugs will have OneHealth implications. Adenosine analogues have shown great promise against both human and veterinary Trypanosoma species, but have generally displayed less activity against Leishmania species. Screening with a Leishmania mexicana cell line defective in adenosine kinase (ADK) shows that the activity of the most potent analogues is dependent on this enzyme, and that activity can be restored and even improved by the experession of T. brucei ADK. Thus, differences in the ADKs of the two species may help explain the differences in antiparasitic activity against the different species, and potentially the high level of specificity regarding mammalian cells as well, Leishmania ADK being substantially different from the equivalent in other eukaryotes [1].
Here, we present results from in silico molecular modeling based on docking for predicting binding poses of antiparasitic nucleoside drugs. The tested hypothesis is whether nucleoside analogues are phosphorylated more easily by TbADK than by Leishmania mexicana (LmxADK). Differences in geometry of active site and ligands conformation were observed, which impact differences in predicted score. The best docking score and the most efficient adenosine analogue in vitro, tubercidin, exerts different patterns of molecular interaction with ligand and amino acid residues in the binding sites of LmxADK and TbADK. Optimising SAR for efficient recognition by the ADKs and adenosine transporters of both Leishmania and Trypanosoma have potential to develop drugs with broad anti-trypanosomatid activity.
[1] Datta AK, Bhaumik D, Chatterjee R. Isolation and characterization of adenosine kinase from Leishmania donovani. J Biol Chem. 1987

Acknowledgment
The Authors acknowledge Cost Action 21111 for financial support in the form of an STSM to A. Cvetkovski, hosted by A. T. García-Sosa.