title: Novel naphthalene-based inhibitors of Trypanosoma brucei RNA editing ligase 1.
abstract: BACKGROUND
  Neglected tropical diseases, including diseases caused by trypanosomatid parasites such as Trypanosoma brucei, cost tens of millions of disability-adjusted life-years annually. As the current treatments for African trypanosomiasis and other similar infections are limited, new therapeutics are urgently needed. RNA Editing Ligase 1 (REL1), a protein unique to trypanosomes and other kinetoplastids, was identified recently as a potential drug target.
  
  
  RESULTS
  Motivated by the urgent need for novel trypanocidal therapeutics, we use an ensemble-based virtual-screening approach to discover new naphthalene-based TbREL1 inhibitors. The predicted binding modes of the active compounds are evaluated within the context of the flexible receptor model and combined with computational fragment mapping to determine the most likely binding mechanisms. Ultimately, four new low-micromolar inhibitors are presented. Three of the four compounds may bind to a newly revealed cleft that represents a putative druggable site not evident in any crystal structure.
  
  
  CONCLUSIONS
  Pending additional optimization, the compounds presented here may serve as precursors for future novel therapies useful in the fight against several trypanosomatid pathogens, including human African trypanosomiasis, a devastating disease that afflicts the vulnerable patient populations of sub-Saharan Africa.
authors.affiliation: Biomedical Sciences Program, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Durrant
authors.forename: Laurence
authors.initials: L
authors.lastname: Hall
authors.forename: Robert V
authors.initials: RV
authors.lastname: Swift
authors.forename: Melissa
authors.initials: M
authors.lastname: Landon
authors.forename: Achim
authors.initials: A
authors.lastname: Schnaufer
authors.forename: Rommie E
authors.initials: RE
authors.lastname: Amaro
mesh_terms: D019729:Carbon-Oxygen Ligases / Q000037:antagonists & inhibitors*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D009281:Naphthalenes / Q000494:pharmacology*; D011485:Protein Binding; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D024101:Mitochondrial Proteins; D009281:Naphthalenes; D014344:Trypanocidal Agents; D019729:Carbon-Oxygen Ligases; C476580:REL1 RNA ligase, Trypanosoma brucei
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