Discovery of protein phosphatase 2C inhibitors by virtual screening

Journal of Medicinal Chemistry
Jessica P RogersP Greengard

Abstract

Protein phosphatase 2C (PP2C) is an archetype of the PPM Ser/Thr phosphatases, characterized by dependence on divalent magnesium or manganese cofactors, absence of known regulatory proteins, and resistance to all known Ser/Thr phosphatase inhibitors. We have used virtual ligand screening with the AutoDock method and the National Cancer Institute Diversity Set to identify small-molecule inhibitors of PP2Calpha activity at a protein substrate. These inhibitors are active in the micromolar range and represent the first non-phosphate-based molecules found to inhibit a type 2C phosphatase. The compounds docked to three recurrent binding sites near the PP2Calpha active site and displayed novel Ser/Thr phosphatase selectivity profiles. Common chemical features of these compounds may form the basis for development of a PP2C inhibitor pharmacophore and may facilitate investigation of PP2C control and cellular function.

References

Jan 1, 1990·Proteins·D S Goodsell, A J Olson
Jan 1, 1989·Annual Review of Biochemistry·P Cohen
Aug 1, 1996·Journal of Computer-aided Molecular Design·G M MorrisA J Olson
Nov 14, 1997·Bioorganic & Medicinal Chemistry·J E SheppeckA R Chamberlin
Jul 1, 1998·Annual Review of Biophysics and Biomolecular Structure·D BarfordM P Egloff
Dec 18, 1998·The Journal of Biological Chemistry·Y TongS H Shen
Jul 10, 1999·The Journal of Biological Chemistry·C C Fjeld, J M Denu
Jan 27, 2000·Cell·T Hunter
Oct 4, 2000·Physiological Reviews·F Rusnak, P Mertz
Dec 6, 2000·The Journal of Biological Chemistry·M HanadaS Tamura
Sep 14, 2001·Biochemical and Biophysical Research Communications·S MitsuhashiK Kikuchi
Jan 25, 2002·Annual Review of Pharmacology and Toxicology·Zhong-Yin Zhang
Feb 22, 2002·Journal of Chemical Information and Computer Sciences·Wolf-Dietrich IhlenfeldtMarc C Nicklaus
Mar 8, 2002·Journal of Medicinal Chemistry·Adam McCluskeyJennette A Sakoff
May 4, 2002·Nature Cell Biology·Philip Cohen
May 17, 2002·Journal of Medicinal Chemistry·Thompson N DomanBrian K Shoichet
May 31, 2002·Journal of Medicinal Chemistry·Daniel F VeberKenneth D Kopple
May 31, 2002·The Journal of Biological Chemistry·Veronique De SmedtRene Ozon
Jul 16, 2002·Proceedings of the National Academy of Sciences of the United States of America·Richard Y T KaoRobert Shapiro
Jul 18, 2002·Nature Reviews. Drug Discovery·Philip Cohen
Jul 18, 2002·Nature Reviews. Drug Discovery·Margaret A Somerville
Sep 6, 2002·Journal of Medicinal Chemistry·Yvonne C MartinLinda M Traphagen
Dec 10, 2002·Science·G ManningS Sudarsanam
Apr 2, 2003·Molecular Cell·Christophe LeroyMarie-Claude Marsolier-Kergoat
May 30, 2003·Biochemical Society Transactions·P Willett
Aug 9, 2003·Journal of Medicinal Chemistry·Krzysztof SwierczekAlvan C Hengge
Sep 25, 2003·Proceedings of the National Academy of Sciences of the United States of America·Masaru OhtaJian-Kang Zhu
Sep 27, 2003·Biochemical and Biophysical Research Communications·James C BurnettSina Bavari
Oct 3, 2003·Journal of Medicinal Chemistry·James SeidlerBrian K Shoichet
Dec 10, 2003·Proceedings of the National Academy of Sciences of the United States of America·Marc FlajoletPaul Greengard
Jan 14, 2004·Nature Structural & Molecular Biology·Rekha G PanchalSina Bavari
Apr 1, 2004·Nature Genetics·René Bernards
May 4, 2004·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·S L Holbeck
May 8, 2004·Trends in Plant Science·Alois SchweighoferIrute Meskiene
May 18, 2004·Proteins·Oliver KraemerGerhard Klebe

❮ Previous
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Citations

Dec 7, 2007·Journal of Structural and Functional Genomics·Steven C AlmoStephen K Burley
Jan 1, 2014·Bioorganic & Medicinal Chemistry·Min Ting LiuKevin Ryan
Dec 4, 2012·Journal of Chemical Information and Modeling·Woong-Hee Shin, Chaok Seok
Mar 25, 2009·Journal of Proteome Research·Aurelio SilvestroniLakshmi Rajagopal
Mar 21, 2009·Molecular Pharmacology·Jamie L McConnell, Brian E Wadzinski
Jan 22, 2009·RNA·Kevin RyanXiaozhou P Ryan
Dec 20, 2012·PloS One·Ankur DhanikLydia E Kavraki
May 3, 2011·Expert Opinion on Drug Discovery·Sandro CosconatiArthur J Olson
Nov 6, 2007·Neuroscience·D Moreno-DelgadoJ Ortiz
Aug 14, 2013·The FEBS Journal·Mengmeng ZhangYan Zhang
Sep 28, 2007·Biochemical and Biophysical Research Communications·Noriyuki SueyoshiAtsuhiko Ishida
Nov 7, 2006·Trends in Neurosciences·Isabelle M Mansuy, Shirish Shenolikar
Jul 5, 2007·Chemistry : a European Journal·Andreas SteffenJoannis Apostolakis
Jul 8, 2008·Chemistry : a European Journal·Patricia G CruzAntonio Hernández Daranas
Jun 6, 2007·The Journal of Biological Chemistry·Kenneth M HumphriesSusan S Taylor
Mar 13, 2014·The Journal of Biological Chemistry·Sébastien MarionMarc G Caron
Jan 7, 2009·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Shuxian SongYuhong Xu
Nov 1, 2006·Biochemical Society Transactions·S KlumppJ Krieglstein
Aug 13, 2011·Journal of Computational Chemistry·Woong-Hee ShinJooyoung Lee
Dec 19, 2020·Gene·Ismael Y KarkacheElizabeth W Bradley
Jul 11, 2020·Pharmacology & Therapeutics·Rui KamadaKazuyasu Sakaguchi
May 9, 2021·Cellular Signalling·Joachim NeumannUlrich Gergs
Dec 5, 2008·Journal of Medicinal Chemistry·Andreja KovacStanislav Gobec
Dec 4, 2021·Experimental Biology and Medicine·Mao LiJianguo Yan

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