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Measuring experimental cyclohexane-water distribution coefficients for the SAMPL5 challenge

Ariën S. Rustenburg, Justin Dancer, Baiwei Lin, Jianwen A. Feng, Daniel F. Ortwine, View ORCID ProfileDavid L. Mobley, John D. Chodera
doi: https://doi.org/10.1101/063081
Ariën S. Rustenburg
1Graduate Program in Physiology, Biophysics, and Systems Biology, Weill Cornell Medical College, New York, NY 10065
2Computational Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States
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Justin Dancer
3Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States
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Baiwei Lin
3Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States
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Jianwen A. Feng
4Denali Therapeutics, 201 Gateway Blvd, South San Francisco, CA 94080, United States
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Daniel F. Ortwine
3Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States
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David L. Mobley
5Department of Pharmaceutical Sciences and Department of Chemistry, University of California, Irvine, Irvine, California 92697, United States
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  • ORCID record for David L. Mobley
John D. Chodera
2Computational Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States
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  • For correspondence: john.chodera@choderalab.org
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Abstract

Small molecule distribution coefficients between immiscible nonaqueuous and aqueous phases—such as cyclohexane and water—measure the degree to which small molecules prefer one phase over another at a given pH. As distribution coefficients capture both thermodynamic effects (the free energy of transfer between phases) and chemical effects (protonation state and tautomer effects in aqueous solution), they provide an exacting test of the thermodynamic and chemical accuracy of physical models without the long correlation times inherent to the prediction of more complex properties of relevance to drug discovery, such as protein-ligand binding affinities. For the SAMPL5 challenge, we carried out a blind prediction exercise in which participants were tasked with the prediction of distribution coefficients to assess its potential as a new route for the evaluation and systematic improvement of predictive physical models. These measurements are typically performed for octanol-water, but we opted to utilize cyclohexane for the nonpolar phase. Cyclohexane was suggested to avoid issues with the high water content and persistent heterogeneous structure of water-saturated octanol phases, since it has greatly reduced water content and a homogeneous liquid structure. Using a modified shake-flask LC-MS/MS protocol, we collected cyclohexane/water distribution coefficients for a set of 53 druglike compounds at pH 7.4. These measurements were used as the basis for the SAMPL5 Distribution Coefficient Challenge, where 18 research groups predicted these measurements before the experimental values reported here were released. In this work, we describe the experimental protocol we utilized for measurement of cyclohexane-water distribution coefficients, report the measured data, propose a new bootstrap-based data analysis procedure to incorporate multiple sources of experimental error, and provide insights to help guide future iterations of this valuable exercise in predictive modeling.

SAMPL
Statistical Assessment of the Modeling of Proteins and Ligands
log P
log 10 partition coefficient
log D
log 10 distribution coefficient
LC-MS/MS
Liquid chromatography - tandem mass spectrometry
HPLC
High-pressure liquid chromatography
MRM
Multiple reaction monitoring
DMSO
Dimethyl sulfoxide
PBS
Phosphate buffered saline
RPM
Revolutions per minute
CV
Coefficient of variation
MAP
Maximum a posteriori
MCMC
Markov chain Monte Carlo
Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted September 28, 2016.
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Measuring experimental cyclohexane-water distribution coefficients for the SAMPL5 challenge
Ariën S. Rustenburg, Justin Dancer, Baiwei Lin, Jianwen A. Feng, Daniel F. Ortwine, David L. Mobley, John D. Chodera
bioRxiv 063081; doi: https://doi.org/10.1101/063081
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Measuring experimental cyclohexane-water distribution coefficients for the SAMPL5 challenge
Ariën S. Rustenburg, Justin Dancer, Baiwei Lin, Jianwen A. Feng, Daniel F. Ortwine, David L. Mobley, John D. Chodera
bioRxiv 063081; doi: https://doi.org/10.1101/063081

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