P. R. O. Whittamore et al. / Bioorg. Med. Chem. Lett. 16 (2006) 5567–5571
5571
8. Oikonomakos, N. G.; Skamnaki, V. T.; Tsitsanou, K. E.;
Gavalas, N. G.; Johnson, L. N. Structure 2000, 8, 575;
Rath, V. L.; Ammirati, M.; Danley, D. E.; Ekstrom, J. L.;
Gibbs, E. M.; Hynes, T. R.; Mathiowetz, A. M.; McPh-
erson, R. K.; Olson, T. V.; Treadway, J. L.; Hoover, D. J.
Chem. Biol. 2000, 7, 677.
hepatocyte activity, synthetic routes and demonstrated
binding at the dimer interface of the rabbit muscle en-
zyme. Lead optimization in these series and pharmaco-
logical profiling of leading compounds will be reported
in due course.
9. For in vitro assay experimental procedures, see: Bartlett, J.
B.; Freeman, S.; Kenny, P. W.; Morley, A. D.; Whitta-
more, P. R. O. PCT Intl Application WO200220530, 2002;
Chem. Abstr. 2002, 136, 247485.
Acknowledgments
Thanks to Sue Freeman, Simon Poucher, Gemma Con-
vey, Julie Bartlett and Jenny Thomas for the bioscience
testing. Richard Pauptit is thanked for establishing the
crystallography collaboration with the Oikonomakos
group, who have kindly provided protein and crystals.
Thanks to Claire Minshull for the soaking experiments
10. Protein crystals kindly provided by N.G.O. were grown
using published procedures.14 Diffraction data were
collected at SRS, Daresbury, at 100 K for compound
17 and at ESRF, Grenoble, at 100 K for compound 15.
The crystals of the complex with 15 have space group
˚
P43212, unit cell 126.8, 126.8, 115.1 A. 39468 unique
˚
reflections to 2.3 A give 97.7% completeness. The final
R-factor is 18.3% (Rfree using 5% of data is 24.5%).
ˆ
and to Jason Breed, Richard Pauptit, Sian Rowsell and
Julie Tucker for synchrotron data collection and analysis.
2
The mean temperature factor is 31.5 A for protein
˚
2
atoms and 47.8 A for the ligand. Crystals of the
˚
complex with 17 have space group P43212 and unit cell
˚
˚
References and notes
128.1, 128.1, 116.3 A. 98,023 unique reflections to 1.6A
give 74.5% completeness. The final model has an R-
factor of 18.7% (Rfree using 5% of data is 22.6%).
Mean atomic temperature factor for the protein is 18.4
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2
˚
and for the inhibitor is 13.7 A . Data analysis and
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Quanta2000 (Accelrys). The model was refined using
CNX(Accelrys) and Refmac5.15 Protein Data Bank
deposition codes for the refined structures 15 and 17
are 2GM9 and 2GJ4, respectively.
´
´
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12. Scheme 2—for further details, see: Butters, M.; Schofield,
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2004; Chem. Abstr. 2004, 140, 339190.
13. Scheme 3—for further details, see: Murray, P. M.;
Parker, J. S.; Schofield, P.; Stocker, A. PCT Intl
Application WO2004031194, 2004; Chem. Abstr. 2004,
140, 339191.
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Biochim. Biophys. Acta 1985, 832, 248.
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