title: Discovery of drug-like inhibitors of an essential RNA-editing ligase in Trypanosoma brucei.
abstract: Trypanosomatid RNA editing is a unique process and essential for these organisms. It therefore represents a drug target for a group of protozoa that includes the causative agents for African sleeping sickness and other devastating tropical and subtropical diseases. Here, we present drug-like inhibitors of a key enzyme in the editing machinery, RNA-editing ligase 1 (REL1). These inhibitors were identified through a strategy employing molecular dynamics to account for protein flexibility. A virtual screen of the REL1 crystal structure against the National Cancer Institute Diversity Set was performed by using AutoDock4. The top 30 compounds, predicted to interact with REL1's ATP-binding pocket, were further refined by using the relaxed complex scheme (RCS), which redocks the compounds to receptor structures extracted from an explicitly solvated molecular dynamics trajectory. The resulting reordering of the ligands and filtering based on drug-like properties resulted in an initial recommended set of 8 ligands, 2 of which exhibited micromolar activity against REL1. A subsequent hierarchical similarity search with the most active compound over the full National Cancer Institute database and RCS rescoring resulted in an additional set of 6 ligands, 2 of which were confirmed as REL1 inhibitors with IC(50) values of approximately 1 microM. Tests of the 3 most promising compounds against the most closely related bacteriophage T4 RNA ligase 2, as well as against human DNA ligase IIIbeta, indicated a considerable degree of selectivity for RNA ligases. These compounds are promising scaffolds for future drug design and discovery efforts against these important pathogens.
authors.affiliation: Department of Chemistry and Biochemistry and Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, CA 92093-0365, USA. ramaro@mccammon.ucsd.edu
authors.forename: Rommie E
authors.initials: RE
authors.lastname: Amaro
authors.forename: Achim
authors.initials: A
authors.lastname: Schnaufer
authors.forename: Heidrun
authors.initials: H
authors.lastname: Interthal
authors.forename: Wim
authors.initials: W
authors.lastname: Hol
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Stuart
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D000818:Animals; D019729:Carbon-Oxygen Ligases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D019295:Computational Biology / Q000379:methods; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000037:antagonists & inhibitors; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015394:Molecular Structure; D000075223:Poly-ADP-Ribose Binding Proteins; D017393:RNA Editing / Q000235:genetics*; D011130:RNA Ligase (ATP) / Q000037:antagonists & inhibitors; D014346:Trypanosoma brucei brucei / Q000378:metabolism*; D014764:Viral Proteins / Q000037:antagonists & inhibitors; D029867:Xenopus Proteins
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D024101:Mitochondrial Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D014764:Viral Proteins; D029867:Xenopus Proteins; D019729:Carbon-Oxygen Ligases; C476580:REL1 RNA ligase, Trypanosoma brucei; D011088:DNA Ligases; D000072481:DNA Ligase ATP; C000618816:DNA ligase III alpha protein, Xenopus; D011130:RNA Ligase (ATP); C467724:bacteriophage T4 RNA ligase 2