A Novel Method for High Throughput Lipophilicity Determination by Microscale Shake Flask and Liquid Chromatography Tandem Mass Spectrometry

Lin, Baiwei; Pease, Joseph

doi:10.2174/1386207311301010007

Cited by 38 publications

(46 citation statements)

References 24 publications

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“…Unfortunately, this compound was inactive in the cell-based assay. We suspect this molecule may be too polar (measured LogD = -0.4 at pH 7.4), 9 to be cellularly permeable. Encouragingly, 2-furyl and 3,4-pyrazole analogs (42 and 43) showed improved KDM5A enzyme inhibition potency relative to 1.…”

mentioning

confidence: 96%

Lead optimization of a pyrazolo[1,5-a]pyrimidin-7(4H)-one scaffold to identify potent, selective and orally bioavailable KDM5 inhibitors suitable for in vivo biological studies

Liang¹,

Zhang²,

Labadie³

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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mentioning

confidence: 96%

Lead optimization of a pyrazolo[1,5-a]pyrimidin-7(4H)-one scaffold to identify potent, selective and orally bioavailable KDM5 inhibitors suitable for in vivo biological studies

Liang¹,

Zhang²,

Labadie³

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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“…Distribution coefficient measurements utilized a shake flask approach based on a liquid chromatography–tandem mass spectrometry (LC–MS/MS) technique previously developed for 1-octanol/water distribution coefficient measurements [21]. The approach is described in Section II B, and the procedure is schematically summarized in Figure 2.…”

Section: Experimental Methodsmentioning

confidence: 99%

“…This selection was expanded to include 31 compounds used as internal standards for the previously developed octanol/water assay protocol [21], bringing the total number of compounds for which measurements were performed to 95. These compounds were randomly assigned numerical SAMPL_XXX designations for the SAMPL5 blind challenge.…”

Section: Experimental Methodsmentioning

confidence: 99%

“…We adapted a shake-flask assay method from an original octanol/water LC-MS/MS protocol [21] to accommodate the use of cyclohexane for the nonaqueous phase. Our modified protocol is described here, and the procedure is explained schematically in Figure 2.…”

Section: Experimental Methodsmentioning

confidence: 99%

“…As part of an internship program at Genentech arranged by the coauthors, the lead author was dispatched to work out modifications of a high-throughput shake-flask protocol [21] currently in use for octanol/water distribution coefficient measurements. In particular, the low dielectric constant of cyclohexane (2.0243) compared to 1-octanol (10.30) [22] and cyclohexane’s surprising ability to dissolve laboratory consumables presented some unexpected challenges.…”

Section: Introductionmentioning

confidence: 99%

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Measuring experimental cyclohexane-water distribution coefficients for the SAMPL5 challenge

Rustenburg

Dancer

Lin³

et al. 2016

J Comput Aided Mol Des

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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 drug like 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.

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Benchmarking Accuracy and Generalizability of Four Graph Neural Networks Using Large In Vitro ADME Datasets from Different Chemical Spaces

Broccatelli¹,

Trager²,

Reutlinger

et al. 2022

Molecular Informatics

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In this work, we benchmark a variety of singleand multi-task graph neural network (GNN) models against lower-bar and higher-bar traditional machine learning approaches employing human engineered molecular features. We consider four GNN variants -Graph Convolutional Network (GCN), Graph Attention Network (GAT), Message Passing Neural Network (MPNN), and Attentive Fingerprint (AttentiveFP). So far deep learning models have been primarily benchmarked using lower-bar traditional models solely based on fingerprints, while more realistic benchmarks employing fingerprints, whole-molecule descriptors and predictions from other related endpoints (e. g., LogD7.4) appear to be scarce for industrial ADME datasets. In addition to time-split test sets based on Genentech data, this study benefits from the availability of measurements from an external chemical space (Roche data). We identify GAT as a promising approach to implementing deep learning models. While all the deep learning models significantly outperform lower-bar benchmark traditional models solely based on fingerprints, only GATs seem to offer a small but consistent improvement over higher-bar benchmark traditional models. Finally, the accuracy of in vitro assays from different laboratories predicting the same experimental endpoints appears to be comparable with the accuracy of GAT single-task models, suggesting that most of the observed error from the models is a function of the experimental error propagation.

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A Novel Method for High Throughput Lipophilicity Determination by Microscale Shake Flask and Liquid Chromatography Tandem Mass Spectrometry

Cited by 38 publications

References 24 publications

Lead optimization of a pyrazolo[1,5-a]pyrimidin-7(4H)-one scaffold to identify potent, selective and orally bioavailable KDM5 inhibitors suitable for in vivo biological studies

Lead optimization of a pyrazolo[1,5-a]pyrimidin-7(4H)-one scaffold to identify potent, selective and orally bioavailable KDM5 inhibitors suitable for in vivo biological studies

Measuring experimental cyclohexane-water distribution coefficients for the SAMPL5 challenge

Benchmarking Accuracy and Generalizability of Four Graph Neural Networks Using Large In Vitro ADME Datasets from Different Chemical Spaces

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