Discovery of Ligands for a Novel Target, the Human Telomerase RNA, Based on Flexible-Target Virtual Screening and NMR

• Published in: Journal of medicinal chemistry Vol. 51; no. 22; pp. 7205 - 7215
• Main Authors: Gómez Pinto, Irene, Guilbert, Christophe, Ulyanov, Nikolai B, Stearns, Jay, James, Thomas L
• Format: Journal Article
• Language: English
• Published: Columbus, OH American Chemical Society 27.11.2008
• Subjects: Aminoquinolines - chemistry; Aminoquinolines - pharmacology; Biological and medical sciences; Computer Simulation; Databases, Factual; Drug Discovery - methods; Heterocyclic Compounds, 4 or More Rings - chemistry; Heterocyclic Compounds, 4 or More Rings - pharmacology; Humans; Ligands; Magnetic Resonance Spectroscopy; Medical sciences; Miscellaneous; Molecular Structure; Molecular Weight; Pharmacology. Drug treatments; Phenothiazines - chemistry; Phenothiazines - pharmacology; Polycyclic Aromatic Hydrocarbons - chemistry; Polycyclic Aromatic Hydrocarbons - pharmacology; Reference Standards; RNA - chemistry; RNA - metabolism; Structure-Activity Relationship; Telomerase - chemistry; Telomerase - metabolism; Human; Biological fixation; Nucleotidyltransferases; RNA; Structure activity relation; Enzyme; Ligand; Transferases; Virtual screening; Affinity; NMR spectrometry; Telomerase
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm800825n

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.