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random starting position and conformation, translation
˚
step ranges of 2.0 A, rotation step ranges of 50ꢁ, elitism
of 1, mutation rate of 0.02, crossover rate of 0.8, local
search rate of 0.06, and 50 million energy evaluations.
Final docked conformations were clustered using a tol-
˚
erance of 1.5 A root-mean-square deviations (RMSD).
5.16. Glide30
Ligand preparation: the molecules were built in Maestro
Suite and were minimized using the OPLS-2005 force-
field. A maximum of 32 stereoisomers were allowed to
generate per ligand. Possible ionization states were
assigned at a target pH of 7.0 2.0. Target preparation:
the homology modeled structure of Leishmania tubulin19
was prepared for docking using the protein preparation
utility provided by Schrodinger LLC. This process opti-
mizes the protonation states and tautomers of His resi-
dues as well as the position of hydroxyl and thiol
hydrogens. The structure was then subjected to impact
´
18. George, T.; Johnsamuel, J.; Delfın, D.; Yakovich, A.;
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Kaiser, M.; Brun, R.; Werbovetz, K. Bioorg. Med. Chem.
2006, 14, 5699–5710.
˚
minimization with a cut off RMSD of 0.3 A. Partial
atomic charges were assigned according to the OPLS-
2005 force field. Molecular Docking: the model was sub-
19. Mitra, A.; Sept, D. J. Med. Chem. 2006, 49, 5226–5231.
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˚
mitted to grid map calculations using a box of 12 A cube
centered on the bound ligand 2b. The consequent docking
has been conducted using the Glide program, with the
default settings using the previously prepared ligands.
The most stable Glide pose, one per ligand, was retained.
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Acknowledgments
25. Dai, Y.; Guo, Y.; Frey, R.; Ji, Z.; Curtin, M.; Ahmed,
A.; Albert, D.; Arnold, L.; Arries, S.; Barlozzari, T.;
Bauch, J.; Bouska, J.; Bousquet, P.; Cunha, G.; Glaser,
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This work was funded by NIH Grant AI061021 (to
K.A.W.). We also thank Dr. David Sept for helpful
comments.
Supplementary data
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data associated with this article can be found, in the on-
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