Inhibition of Leishmania major pteridine reductase by 2,4,6-triaminoquinazoline: structure of the NADPH ternary complex

Acta Crystallographica. Section D, Biological Crystallography
Karen McLuskeyWilliam N Hunter

Abstract

The structure of Leishmania major pteridine reductase (PTR1) in complex with NADPH and the inhibitor 2,4,6-triaminoquinazoline (TAQ) has been solved in a new crystal form by molecular replacement and refined to 2.6 A resolution. The inhibitor mimics a fragment, the pterin head group, of the archetypal antifolate drug methotrexate (MTX) and exploits similar chemical features to bind in the PTR1 active site. Despite being a much smaller molecule, TAQ displays a similar inhibition constant to that of MTX. PTR1 is a target for the development of improved therapies for infections caused by trypanosomatid parasites and this analysis provides information to assist the structure-based development of novel enzyme inhibitors.

Citations

Feb 5, 2008·Proceedings of the National Academy of Sciences of the United States of America·Antonio CavazzutiMaria Paola Costi
Jan 6, 2011·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Keri L BarrackWilliam N Hunter
Oct 23, 2013·Future Medicinal Chemistry·Ifedayo Victor OgungbeWilliam N Setzer
Jul 5, 2013·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ifedayo Victor Ogungbe, William N Setzer
Sep 20, 2005·Journal of Structural Biology·Norbert SchormannDebasish Chattopadhyay
Jan 13, 2015·European Journal of Medicinal Chemistry·Cesar Mendoza-MartínezFrancisco Hernández-Luis
Jul 12, 2008·Experimental Parasitology·Pranav KumarNeeloo Singh
Apr 23, 2015·European Journal of Medicinal Chemistry·César Mendoza-MartínezFrancisco Hernández-Luis
Jan 28, 2014·Journal of Molecular Graphics & Modelling·Ifedayo Victor OgungbeWilliam N Setzer
Jun 6, 2014·ACS Medicinal Chemistry Letters·Kuldeep ChauhanPrem M S Chauhan
Oct 25, 2016·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ifedayo Victor Ogungbe, William N Setzer
Aug 3, 2019·Future Medicinal Chemistry·Gustavo Machado das NevesVera L Eifler-Lima
Oct 25, 2007·Biochemical Society Transactions·W N Hunter

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