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Prediction of pKa Using Machine Learning Methods with Rooted Topological Torsion Fingerprints: Application to Aliphatic Amines.

Lu, Yipin and Anand, Shankara and Shirley, William and Gedeck, Peter and Kelley, Brian P and Skolnik, Suzanne and Rodde, Stephane and Nguyen, Mai and Lindvall, Mika and Jia, Weiping (2019) Prediction of pKa Using Machine Learning Methods with Rooted Topological Torsion Fingerprints: Application to Aliphatic Amines. Journal of chemical information and modeling, 59 (11). pp. 4706-4719. ISSN 1549-960X

Abstract

The acid-base dissociation constant, p, is a key parameter to define the ionization state of a compound and directly affects its biopharmaceutical profile. In this study, we developed a novel approach for p prediction using rooted topological torsion fingerprints in combination with five machine learning (ML) methods: random forest, partial least squares, extreme gradient boosting, lasso regression, and support vector regression. With a large and diverse set of 14 499 experimental p values, p models were developed for aliphatic amines. The models demonstrated consistently good prediction statistics and were able to generate accurate prospective predictions as validated with an external test set of 726 p values (RMSE 0.45, MAE 0.33, and 0.84 by the top model). The factors that may affect prediction accuracy and model applicability were carefully assessed. The results demonstrated that rooted topological torsion fingerprints coupled with ML methods provide a promising approach for developing accurate p prediction models.

Item Type: Article
Date Deposited: 28 Jan 2020 00:45
Last Modified: 28 Jan 2020 00:45
URI: https://oak.novartis.com/id/eprint/41954

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