Fragment-based screening by X-ray crystallography, MS and isothermal titration calorimetry to identify PNMT (phenylethanolamine N-methyltransferase) inhibitors

Drinkwater, Nyssa, Vu, Hoan, Lovell, Kimberly M., Criscione, Kevin R., Collins, Brett M., Prisinzano, Thomas E., Pulsen, Sally‑Ann, McLeish, Michael J., Grunewald, Gary L. and Martin, Jennifer L. (2010) Fragment-based screening by X-ray crystallography, MS and isothermal titration calorimetry to identify PNMT (phenylethanolamine N-methyltransferase) inhibitors. Biochemical Journal, 431 1: 51-61. doi:10.1042/BJ20100651

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Author Drinkwater, Nyssa
Vu, Hoan
Lovell, Kimberly M.
Criscione, Kevin R.
Collins, Brett M.
Prisinzano, Thomas E.
Pulsen, Sally‑Ann
McLeish, Michael J.
Grunewald, Gary L.
Martin, Jennifer L.
Title Fragment-based screening by X-ray crystallography, MS and isothermal titration calorimetry to identify PNMT (phenylethanolamine N-methyltransferase) inhibitors
Journal name Biochemical Journal   Check publisher's open access policy
ISSN 0006-2936
0264-6021
Publication date 2010-10-01
Year available 2010
Sub-type Article (original research)
DOI 10.1042/BJ20100651
Volume 431
Issue 1
Start page 51
End page 61
Total pages 11
Place of publication London, U.K.
Publisher Portland Press
Collection year 2011
Language eng
Abstract CNS (central nervous system) adrenaline (epinephrine) is implicated in a wide range of physiological and pathological conditions. PNMT (phenylethanolamine N-methyltransferase) catalyses the final step in the biosynthesis of adrenaline, the conversion of noradrenaline (norepinephrine) to adrenaline by methylation. To help elucidate the role of CNS adrenaline, and to develop potential drug leads, potent, selective and CNS-active inhibitors are required. The fragment screening approach has advantages over other lead discovery methods including high hit rates, more efficient hits and the ability to sample chemical diversity more easily. In the present study we applied fragment-based screening approaches to the enzyme PNMT. We used crystallography as the primary screen and identified 12 hits from a small commercial library of 384 drug-like fragments. The hits include nine chemicals with two fused rings and three single-ring chemical systems. Eight of the hits come from three chemical classes: benzimidazoles (a known class of PNMT inhibitor), purines and quinolines. Nine of the hits have measurable binding affinities (∼5-700 μM) as determined by isothermal titration calorimetry and all nine have ligand efficiencies of 0.39 kcal/mol per heavy atom or better (1 kcal ≈4.184 kJ). We synthesized five elaborated benzimidazole compounds and characterized their binding to PNMT, showing for the first time how this class of inhibitors interact with the noradrenaline-binding site. Finally, we performed a pilot study with PNMT for fragment-based screening by MS showing that this approach could be used as a fast and efficient first-pass screening method prior to characterization of binding mode and affinity of hits. © The Authors Journal compilation © 2010 Biochemical Society.
Keyword Benzimidazole
Catecholamine
Drug discovery
Enzyme inhibition
Fragment-based screening
Phenylethanolamine n-methyltransferase (pnmt)
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
Institute for Molecular Bioscience - Publications
 
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Created: Wed, 17 Nov 2010, 07:58:51 EST by Professor Jenny Martin on behalf of Institute for Molecular Bioscience