ACS Medicinal Chemistry Letters
Letter
(11) Guimaraes, C. R. W.; Cardozo, M. MM-GB/SA rescoring of
docking poses in structure-based lead optimization. J. Chem. Inf. Model.
2008, 48, 958−970.
(12) Abel, R.; Young, T.; Farid, R.; Berne, B. J.; Friesner, R. A. Role
of the Active-Site Solvent in the Thermodynamics of Factor Xa Ligand
Binding. J. Am. Chem. Soc. 2008, 130, 2817−2831.
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AUTHOR INFORMATION
Corresponding Author
Notes
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The authors declare no competing financial interest.
(13) Di, L.; Whitney-Pickett, C.; Umland, J. P.; Zhang, H.; Zhang, X.;
Gebhard, D. F.; Lai, Y.; Federico, J. J., 3rd; Davidson, R. E.; Smith, R.;
Reyner, E. L.; Lee, C.; Feng, B.; Rotter, C.; Varma, M. V.; Kempshall,
S.; Fenner, K.; El-Kattan, A. F.; Liston, T. E.; Troutman, M. D.
Development of a new permeability assay using low-efflux MDCKII
cells. J. Pharm. Sci. 2011, 100, 4974−4985.
ACKNOWLEDGMENTS
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We thank Amit Kalgutkar and Tim Ryder for analysis of the
metabolite ID experiments, and John C. Kath, Michael Robbins
and Robert G. Linde for early work on this project.
(14) Patricelli, M. P.; Nomanbhoy, T. K.; Wu, J.; Brown, H.; Zhou,
D.; Zhang, J.; Jagannathan, S.; Aban, A.; Okerberg, E.; Herring, C.;
Nordin, B.; Helge, W.; Yang, Q.; Lee, J. − D.; Gray, N.; Kozarich, J. W.
In situ kinase profiling reveals functionally relevant properties of native
kinases. Chem. Biol. 2011, 18, 699−710.
(15) Varma, M. V.; Gardner, I.; Steyn, S. J.; Nkansah, P.; Rotter, C. J.;
Whitney-Pickett, C.; Zhang, H.; Di, L.; Cram, M.; Fenner, K. S.; El-
Kattan, A. F. pH-Dependent solubility and permeability criteria for
provisional biopharmaceutics classification (BCS and BDDCS) in early
drug discovery. Mol. Pharmaceutics 2012, 9, 1199−1212.
(16) Orr, S. T.; Rip, S. L.; Ballard, T. E.; Henderson, J. L.; Scott, D.
O.; Obach, R. S.; Sun, H.; Kalgutkar, A. S. Mechanism-Based
Inactivation (MBI) of Cytochrome P450 Enzymes: Structure−Activity
Relationships and Discovery Strategies To Mitigate Drug−Drug
Interaction Risks. J. Med. Chem. 2012, 55, 4896−4933.
(17) Benbow, J. W.; Aubrecht, J.; Banker, M. J.; Nettleton, D.; Aleo,
M. D. Predicting safety toleration of pharmaceutical chemical leads:
cytotoxicity correlations to exploratory toxicity studies. Toxicol. Lett.
2010, 197, 175−182.
(18) Aubrecht, J.; Osowski, J. J.; Persaud, P.; Cheung, J. R.;
Ackerman, J.; Lopes, S. H.; Ku, W. W. Bioluminescent Salmonella
reverse mutation assay: a screen for detecting mutagenicity with high
throughput attributes. Mutagenesis 2007, 22, 335−342.
ABBREVIATIONS
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MW, molecular weight; TPSA, topological polar surface area;
HLM, human liver microsomes; LPS, lipopolysaccharide; dppf,
1,1′-Bis(diphenylphosphino)ferrocene; B2Pin2, Bis(pinacolato)-
diboron; hERG, human ether-a-go-go-related gene; PK,
pharmacokinetic; TDI, time-dependent inhibition; MM-GB/
SA, molecular mechanics with generalized born/surface area
solvation; ND, not determined
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