Rethinking the applicability domain analysis in QSAR models
Journal
Journal of Computer-Aided Molecular Design
ISSN
0920-654X
1573-4951
Publisher
Springer
Date Issued
2024
Author(s)
Mora, Jose R.
Marquez, Edgar A.
Pérez-Pérez, Noel
Contreras-Torres, Ernesto
Perez-Castillo, Yunierkis
Agüero-Chapin, Guillermin
Barigye, Stephen J.
Type
text::journal::journal article
Abstract
Notwithstanding the wide adoption of the OECD principles (or best practices) for QSAR modeling, disparities between in silico predictions and experimental results are frequent, suggesting that model predictions are often too optimistic. Of these OECD principles, the applicability domain (AD) estimation has been recognized in several reports in the literature to be one of the most challenging, implying that the actual reliability measures of model predictions are often unreliable. Applying tree-based error analysis workflows on 5 QSAR models reported in the literature and available in the QsarDB repository, i.e., androgen receptor bioactivity (agonists, antagonists, and binders, respectively) and membrane permeability (highest membrane permeability and the intrinsic permeability), we demonstrate that predictions erroneously tagged as reliable (AD prediction errors) overwhelmingly correspond to instances in subspaces (cohorts) with the highest prediction error rates, highlighting the inhomogeneity of the AD space. In this sense, we call for more stringent AD analysis guidelines which require the incorporation of model error analysis schemes, to provide critical insight on the reliability of underlying AD algorithms. Additionally, any selected AD method should be rigorously validated to demonstrate its suitability for the model space over which it is applied. These steps will ultimately contribute to more accurate estimations of the reliability of model predictions. Finally, error analysis may also be useful in “rational” model refinement in that data expansion efforts and model retraining are focused on cohorts with the highest error rates. © 2024 Springer Nature
How to cite
Mora, J.R., Marquez, E.A., Pérez-Pérez, N. et al. Rethinking the applicability domain analysis in QSAR models. J Comput Aided Mol Des 38, 9 (2024). https://doi.org/10.1007/s10822-024-00550-8