title: Exploration of New and Potent Lead Molecules Against CAAX Prenyl Protease I of Leishmania donovani Through Pharmacophore Based Virtual Screening Approach.
abstract: OBJECTIVE
  Visceral leishmaniasis is a deadly disease left untreated in over 95% of cases. It is characterized by irregular bouts of fever, weight loss, enlargement of the spleen and liver, and anemia. It is highly endemic in the Indian subcontinent. CAAX prenyl protease I of Leishmania donovani is one of the important targets regulating the post translational modification process. Hence identifying potent drug candidate against the target is essential. This study mainly focuses on developing new and potent inhibitors against CAXX prenyl protease I of Leishmania donovani.
  
  
  METHODS
  Pharmacophore based virtual screening was carried out using derivatives of bi-substrate analog farnesyl transferase inhibitors reported against CAAX prenyl proteases I. On the basis of ligand based pharmacophore model we have obtained 5 point pharmacophore AAADR with three hydrogen bond acceptors (A), one hydrogen bond donor (D) and one aromatic ring. The newly identified hits through pharmacophore model were further docked into the active site of the modeled protein. To get further insights of protein ligand interaction we have performed induced fit docking followed by molecular dynamics simulations. The DFT analysis depicts the electronic structure properties of the compounds. These results can be useful for the development of novel and potent CAAX prenyl protease I inhibitors.
  
  
  RESULTS
  Initially, we have obtained a large number of newly identified hits by screening four different databases further docked into the active site of the protein and 20 compounds were selected on the basis of docking score. Perhaps Induced fit docking was performed to infer protein ligand interaction in a dynamic state and top 5 compounds 7118044, 7806909, LEG12866807, 9208535, SYN 19867403 were found to have good protein ligand interactions with key amino acid residues such as Glu287, His290 and additional interaction like Ile197, Asn209 Tyr253, Phe254, Gly256, Tyr266 with better binding energy -59.794 Kcal/mol, -66.305 Kcal/mol, -70.467 Kcal/mol, -82.474 Kcal/mol, -64.045. The predicted ADME properties are in desirable range and the HOMO/LUMO gap clearly indicates the electrons behavior of the ligands. Molecular dynamics simulations of the protein ligand complex for 20 ns clearly depicts the compounds are stable throughout the simulation time.
  
  
  CONCLUSIONS
  The newly identified hits through pharmacophore based screening could be used as potential CAAX prenyl protease I inhibitors of Leishmania donovani.
authors.affiliation: Computer Aided Drug Designing and Molecular Modeling Laboratory, Department of Bioinformatics, Alagappa University, Karaikudi, Tamil Nadu-630 004, India.
authors.forename: Sitrarasu Vijaya
authors.initials: SV
authors.lastname: Prabhu
authors.affiliation: Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam-781039, India.
authors.forename: Kartikeya
authors.initials: K
authors.lastname: Tiwari
authors.affiliation: Computer Aided Drug Designing and Molecular Modeling Laboratory, Department of Bioinformatics, Alagappa University, Karaikudi, Tamil Nadu-630 004, India.
authors.forename: Venkatesan
authors.initials: V
authors.lastname: Suryanarayanan
authors.affiliation: Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam-781039, India.
authors.forename: Vikash Kumar
authors.initials: VK
authors.lastname: Dubey
authors.affiliation: Computer Aided Drug Designing and Molecular Modeling Laboratory, Department of Bioinformatics, Alagappa University, Karaikudi, Tamil Nadu-630 004, India.
authors.forename: Sanjeev Kumar
authors.initials: SK
authors.lastname: Singh
mesh_terms: D055808:Drug Discovery; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D057166:High-Throughput Screening Assays; D006801:Humans; D006860:Hydrogen Bonding; D007893:Leishmania donovani / Q000201:enzymology*; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010447:Peptide Hydrolases / Q000378:metabolism; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011485:Protein Binding; D015800:Protozoan Proteins
chemical_list: D008024:Ligands; D011480:Protease Inhibitors; D015800:Protozoan Proteins; D051231:Farnesyltranstransferase; D010447:Peptide Hydrolases
keywords: CAAX prenyl protease I; density functional theory; electrostatic potential; molecular dynamics simulations; pharmacophore; virtual screening