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

Abstract
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.
AuthorsAbhinav Grover, Shashank Prakash Katiyar, Sanjeev Kumar Singh, Vikash Kumar Dubey, Durai Sundar
JournalBiochimica et biophysica acta (Biochim Biophys Acta) Vol. 1824 Issue 12 Pg. 1476-83 (Dec 2012) ISSN: 0006-3002 [Print] Netherlands
PMID22684087 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Elsevier B.V. All rights reserved.
Chemical References
  • Enzyme Inhibitors
  • Spermidine Synthase
Topics
  • Binding Sites
  • Enzyme Inhibitors (pharmacology)
  • High-Throughput Screening Assays
  • Leishmania donovani (enzymology)
  • Leishmaniasis (drug therapy)
  • Molecular Dynamics Simulation
  • Spermidine Synthase (antagonists & inhibitors, chemistry)
  • Trypanosoma cruzi (enzymology)

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