Discovery of drug-like inhibitors of an essential RNA-editing ligase in Trypanosoma brucei

被引:101
作者
Amaro, Rommie E. [1 ,2 ]
Schnaufer, Achim [3 ]
Interthal, Heidrun [4 ]
Hol, Wim [5 ,6 ,7 ]
Stuart, Kenneth D. [3 ,8 ]
McCammon, J. Andrew [1 ,2 ,9 ,10 ]
机构
[1] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Ctr Theoret Biol Phys, La Jolla, CA 92093 USA
[3] Seattle Biomed Res Inst, Seattle, WA 98109 USA
[4] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA
[5] Univ Washington, Dept Biochem, Seattle, WA 98195 USA
[6] Univ Washington, Biomol Struct Ctr, Seattle, WA 98195 USA
[7] Univ Washington, Biomol Struct & Design BMSD Grad Program, Seattle, WA 98195 USA
[8] Univ Washington, Dept Pathobiol, Seattle, WA 98195 USA
[9] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA
[10] Univ Calif San Diego, Howard Hughes Med Inst, La Jolla, CA 92093 USA
基金
英国医学研究理事会; 美国国家卫生研究院; 美国国家科学基金会;
关键词
molecular dynamics; relaxed complex scheme; RNA ligase; African sleeping sickness; receptor flexibility;
D O I
10.1073/pnas.0805820105
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:17278 / 17283
页数:6
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