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A probabilistic method to report predictions from a human liver microsomes stability QSAR model: a practical tool for drug discovery

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Abstract

Using data from the in vitro liver microsomes metabolic stability assay, we have developed QSAR models to predict in vitro human clearance. Models were trained using in house high-throughput assay data reported as the predicted human hepatic clearance by liver microsomes or pCLh. Machine learning regression methods were used to generate the models. Model output for a given molecule was reported as its probability of being metabolically stable, thus allowing for synthesis prioritization based on this prediction. Use of probability, instead of the regression value or categories, has been found to be an efficient way for both reporting and assessing predictions. Model performance is evaluated using prospective validation. These models have been integrated into a number of desktop tools, and the models are routinely used to prioritize the synthesis of compounds. We discuss two therapeutic projects at Genentech that exemplify the benefits of a probabilistic approach in applying the models. A three-year retrospective analysis of measured liver microsomes stability data on all registered compounds at Genentech reveals that the use of these models has resulted in an improved metabolic stability profile of synthesized compounds.

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Acknowledgments

Jason S. Halladay, Ning Liu, Suzanne Tay, Mika Kosaka, and Jane Lovelidge have developed the in house robust LMs stability assays. We thank Marcel Hop from the DMPK department and Bruce Roth from Discovery Chemistry for their support, Jane Kenny from DMPK for her active role in promoting the use of the models across project teams, Fabio Broccatelli for his assistance in curating the external dataset, Jianwen Feng for integrating the model in various desktop tools, Joachim Rudolph from Discovery Chemistry, and Ronitte Libedinsky for her editorial support.

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Authors and Affiliations

  1. Discovery Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA

    Ignacio Aliagas, Alberto Gobbi, Timothy Heffron, Man-Ling Lee, Daniel F. Ortwine & Mark Zak

  2. Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA

    S. Cyrus Khojasteh

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  1. Ignacio Aliagas
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  2. Alberto Gobbi
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  3. Timothy Heffron
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  7. S. Cyrus Khojasteh
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Correspondence to Ignacio Aliagas.

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Aliagas, I., Gobbi, A., Heffron, T. et al. A probabilistic method to report predictions from a human liver microsomes stability QSAR model: a practical tool for drug discovery. J Comput Aided Mol Des 29, 327–338 (2015). https://doi.org/10.1007/s10822-015-9838-3

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