Protozoa Leishmania donovani (Ld) is the main cause of the endemic disease
leishmaniasis.
Spermidine synthase (SS), an important
enzyme in the synthetic pathway of
polyamines in Ld, is an essential
element for the survival of this protozoan. Targeting SS may provide an important aid for the development of drugs against Ld. However, absence of tertiary structure of
spermidine synthase of Leishmania donovani (LSS) limits the possibilities of structure based
drug designing. Presence of the same
enzyme in the host itself further challenges the
drug development process. We modeled the tertiary structure of LSS using homology modeling approach making use of homologous X-ray crystallographic structure of
spermidine synthase of Trypanosoma cruzi (TSS) (2.5Å resolution). The modeled structure was stabilized using Molecular Dynamics simulations. Based on active site structural differences between LSS and human
spermidine synthase (HSS), we screened a large dataset of compounds against modeled
protein using Glide virtual screen docking and selected two best inhibitors based on their docking scores (-10.04 and -13.11 respectively) with LSS and having least/no binding with the human
enzyme. Finally Molecular Dynamics simulations were used to assess the dynamic stability of the
ligand bound structures and to elaborate on the binding modes. This article is part of a Special Issue entitled: Computational Methods for
Protein Interaction and Structural Prediction.