Discovery of ligands for a novel target, the human telomerase RNA, based on flexible-target virtual screening and NMR.

Discovery of ligands for a novel target, the human telomerase RNA, based on flexible-target virtual screening and NMR.
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基于灵活靶点虚拟筛选和 NMR,发现新靶点——人端粒酶 RNA 的配体。

DOI:
10.1021/jm800825n
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发表时间:
2008
影响因子:
7.3
通讯作者:
James,ThomasL
James,ThomasL
中科院分区:
医学1区
文献类型:
--
作者:
Pinto,IreneGómez;Guilbert,Christophe;Ulyanov,NikolaiB;Stearns,Jay;James,ThomasL

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The human ribonucleoprotein telomerase is a validated anticancer drug target, and hTR-P2b is a part of the human telomerase RNA (hTR) essential for its activity. Interesting ligands that bind hTR-P2b were identified by iteratively using a tandem structure-based approach: docking of potential ligands from small databases to hTR-P2b via the program MORDOR, which permits flexibility in both ligand and target, with subsequent NMR screening of high-ranking compounds. A high percentage of the compounds tested experimentally were found via NMR to bind to the U-rich region of hTR-P2b; most have MW < 500 Da and are from different compound classes, and several possess a charge of 0 or +1. Of the 48 ligands identified, 24 exhibit a decided preference to bind hTR-P2b RNA rather than A-site rRNA and 10 do not bind A-site rRNA at all. Binding affinity was measured by monitoring RNA imino proton resonances for some of the compounds that showed hTR binding preference.
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