A leishmaniasis study: Structure-based screening and molecular dynamics mechanistic analysis for discovering potent inhibitors of spermidine synthase

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) (2.5 Å 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.

► Spermidine Synthase is an essential enzyme for the survival of Leishmania donovani
► We modeled the tertiary structure of leishmanial spermidine synthase using homology based protein modeling technique
► Comparative structural differences in the active site of spermidine synthase from leishmanial and human origin were revealed
► A large dataset of compounds was screened based on these structural differences between the two enzymes
► We report two potent compounds which significantly inhibit leishmanial spermidine synthase along with least/no inhibition of human spermidine synthase