Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 45, Pages 17278-17283Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0805820105
Keywords
molecular dynamics; relaxed complex scheme; RNA ligase; African sleeping sickness; receptor flexibility
Categories
Funding
- National Institutes of Health [F32-GM077729, A1069057, NS061733, GM42188, GM31749]
- National Science Foundation [MRAC CHE060073N, MCB-0506593, MCA935013]
- Howard Hughes Medical Institute
- San Diego Supercomputing Center
- W.M. Keck Foundation
- Accelrys, Inc.
- National Biomedical Computational Resource
- Center for Theoretical Biological Physics
- MRC [G0700257] Funding Source: UKRI
- Medical Research Council [G0700257] Funding Source: researchfish
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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 (REL 1). These inhibitors were identified through a strategy employing molecular dynamics to account for protein flexibility. A virtual screen of the REL 1 crystal structure against the National Cancer Institute Diversity Set was performed by using AutoDock4. The top 30 compounds, predicted to interact with REL 1'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 REL 1. 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 REL 1 inhibitors with IC50 values of approximate to 1 mu M. Tests of the 3 most promising compounds against the most closely related bacteriophage T4 RNA ligase 2, as well as against human DNA ligase III beta, 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.
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