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MedChemComm
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DOI: 10.1039/C6MD00531D
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ARTICLE
significant improvement in the activity towards Plasmodium M. A. J. Ferguson, D. F. Smith and P. G. Wyatt, Nature, 2010, 464,
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activities against both PvNMT and PfNMT. Moreover,
controlling the lipophilicity as part of the optimization process
allowed us to identify novels inhibitors with significantly improved
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The low selectivity over host NMT may limit the potential to
progress this series to lead optimisation.36 However, we recently
reported that ligands that induce conformational changes in Tyr211
10. E. W. Tate, A. S. Bell, M. D. Rackham and M. H. Wright,
of PvNMT were selective for Plasmodium NMTs over human
Parasitology, 2014, 141, 37ꢀ49.
NMT,9 and further investigation of the 4ꢀposition of the quinoline,
which is in contact with Tyr211, may be a fruitful area for future 11. M. H. Wright, B. Clough, M. D. Rackham, K. Rangachari, J. A.
exploration.
Brannigan, M. Grainger, D. K. Moss, A. R. Bottrill, W. P. Heal, M.
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Finally, we expect that the crystal structures obtained as part of this
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series of inhibitors targeting NMT.18ꢀ35
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13. E. Thinon, J. MoralesꢀSanfrutos, D. J. Mann and E. W. Tate,
ACS Chem. Biol., 2016, DOI: 10.1021/acschembio.6b00371.
Notes
The authors declare no competing financial interest.
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Acknowledgements
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The authors are grateful to Mark Rackham, Zhiyong Yu and Jennie
Hutton for valuable discussions. We thank Diamond Light Source
for access to beamlines I02 and I04 (proposal numbers mxꢀ1221 and
mxꢀ7864). This work was supported by the Medical Research
Council (grants G0900278 and U117532067), the EPSRC (grant
EP/F500416/1) and the Wellcome Trust (grant 087792).
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