title: In silico identification of promiscuous scaffolds as potential inhibitors of 1-deoxy-d-xylulose 5-phosphate reductoisomerase for treatment of Falciparum malaria.
abstract: BACKGROUND
  Malaria remains one of the prevalent infectious diseases worldwide. Plasmodium falciparum 1-deoxy-d-xylulose-5-phosphate reductoisomerase (PfDXR) plays a role in isoprenoid biosynthesis in the malaria parasite, making this parasite enzyme an attractive target for antimalarial drug design. Fosmidomycin is a promising DXR inhibitor, which showed safety as well as efficacy against Plasmodium falciparum malaria in clinical trials. However, due to its poor oral bioavailability and non-drug-like properties, the focus of medicinal chemists is to develop inhibitors with improved pharmacological properties.
  
  
  OBJECTIVE
  This study described the computational design of new and potent inhibitors for deoxyxylulose 5-phosphate reductoisomerase and the prediction of their pharmacokinetic and pharmacodynamic properties.
  
  
  METHODS
  A complex-based pharmacophore model was generated from the complex X-ray crystallographic structure of PfDXR using MOE (Molecular Operating Environment). Furthermore, MOE-Dock was used as docking software to predict the binding modes of hits and target enzyme.
  
  
  RESULTS
  Finally, 14 compounds were selected as new and potent inhibitors of PfDXR on the basis of pharmacophore mapping, docking score, binding energy and binding interactions with the active site residues of the target protein. The predicted pharmacokinetic properties showed improved permeability by efficiently crossing blood-brain barrier. While, in silico promiscuity binding data revealed that these hits also have the ability to bind with other P. falciparum drug targets.
  
  
  CONCLUSIONS
  In conclusion, innovative scaffolds with novel modes of action, improved efficacy and acceptable physiochemical/pharmacokinetic properties were computationally identified.
authors.affiliation: a Department of Biochemistry , Abdul Wali Khan University Mardan , Mardan , Pakistan.
authors.forename: Abdul
authors.initials: A
authors.lastname: Wadood
authors.affiliation: a Department of Biochemistry , Abdul Wali Khan University Mardan , Mardan , Pakistan.
authors.forename: Mehreen
authors.initials: M
authors.lastname: Ghufran
authors.affiliation: b Department of Pharmacy , University of Lahore , Lahore , Pakistan.
authors.forename: Syed Fahad
authors.initials: SF
authors.lastname: Hassan
authors.affiliation: a Department of Biochemistry , Abdul Wali Khan University Mardan , Mardan , Pakistan.
authors.forename: Huma
authors.initials: H
authors.lastname: Khan
authors.affiliation: c Department of Bioinformatics , Quaid-i-Azam University , Islamabad , Pakistan.
authors.forename: Syed Sikandar
authors.initials: SS
authors.lastname: Azam
authors.affiliation: d Department of Chemistry , COMSAT , Abbatabad , Pakistan.
authors.forename: Umer
authors.initials: U
authors.lastname: Rashid
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000962:Antimalarials / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001665:Binding Sites; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000378:metabolism; D017076:Computer-Aided Design; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008954:Models, Biological; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010539:Permeability; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D011485:Protein Binding; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases
keywords: Molecular docking; pharmacokinetics and pharmacodynamics properties; virtual screening