title: Benefit of Retraining pKa Models Studied Using Internally Measured Data.
abstract: The ionization state of drugs influences many pharmaceutical properties such as their solubility, permeability, and biological activity. It is therefore important to understand the structure property relationship for the acid-base dissociation constant pKa during the lead optimization process to make better-informed design decisions. Computational approaches, such as implemented in MoKa, can help with this; however, they often predict with too large error especially for proprietary compounds. In this contribution, we look at how retraining helps to greatly improve prediction error. Using a longitudinal study with data measured over 15 years in a drug discovery environment, we assess the impact of model training on prediction accuracy and look at model degradation over time. Using the MoKa software, we will demonstrate that regular retraining is required to address changes in chemical space leading to model degradation over six to nine months.
authors.affiliation: †Novartis Institute for Tropical Diseases Pte. Ltd., 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore.
authors.forename: Peter
authors.initials: P
authors.lastname: Gedeck
authors.affiliation: ‡Novartis Institute for Biomedical Research, 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Yipin
authors.initials: Y
authors.lastname: Lu
authors.affiliation: §Novartis Institute for Biomedical Research, 250 Massachusetts Ave, Cambridge, Massachusetts 02139, United States.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Skolnik
authors.affiliation: ∥Novartis Institute for Biomedical Research, Postfach, CH-4002 Basel, Switzerland.
authors.forename: Stephane
authors.initials: S
authors.lastname: Rodde
authors.affiliation: ‡Novartis Institute for Biomedical Research, 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Gavin
authors.initials: G
authors.lastname: Dollinger
authors.affiliation: ‡Novartis Institute for Biomedical Research, 5300 Chiron Way, Emeryville, California 94608, United States.
authors.forename: Weiping
authors.initials: W
authors.lastname: Jia
authors.affiliation: §Novartis Institute for Biomedical Research, 250 Massachusetts Ave, Cambridge, Massachusetts 02139, United States.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Berellini
authors.affiliation: ∥Novartis Institute for Biomedical Research, Postfach, CH-4002 Basel, Switzerland.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Vianello
authors.affiliation: ∥Novartis Institute for Biomedical Research, Postfach, CH-4002 Basel, Switzerland.
authors.forename: Bernard
authors.initials: B
authors.lastname: Faller
authors.affiliation: §Novartis Institute for Biomedical Research, 250 Massachusetts Ave, Cambridge, Massachusetts 02139, United States.
authors.forename: Franco
authors.initials: F
authors.lastname: Lombardo
mesh_terms: D055598:Chemical Phenomena; D000069550:Machine Learning; D008962:Models, Theoretical; D015203:Reproducibility of Results