Identification of two natural compound inhibitors of Leishmania donovani Spermidine Synthase (SpdS) through molecular docking and dynamic studies.

Visceral leishmaniasis caused by the protozoan Leishmania donovani is the most severe form of leishmaniasis and it is potentially lethal if untreated. Despite the availability of drugs for treating the disease, the current drug regime suffers from drawbacks like antibiotic resistance and toxicity. New drugs have to be discovered in order to overcome these limitations. Our aim is to identify natural compounds from plant sources as putative inhibitors considering the occurrence of structural diversity in plant sources. Spermidine Synthase (SpdS) was chosen as the target enzyme as it plays a vital role in growth, survival, and due to its contribution in virulence. Our initial investigation started with a literature survey in identifying natural compounds that showed antileishmanial activity. Subsequently, we identified two monoterpenoid compounds, namely Geraniol and Linalool, that were structurally analogous to one of the substrates (putrescine) of SpdS. In the present study, homology model of L. donovani SpdS was generated and the binding affinity of the identified compounds was analyzed and also compared with the putrescine through molecular docking and dynamic studies. The pharmacokinetic properties of the identified compounds were validated and the binding efficiency of these ligands over the original substrate has been demonstrated. Based on these studies, Geraniol and Linalool can be considered as lead molecules for future investigations targeting SpdS. This study further emphasizes the choice of natural compounds as a good source of therapeutic agents.