ADMET Predictability at Boehringer Ingelheim: State-of-the-Art, and Do Bigger Datasets or Algorithms Make a Difference?

Abstract

Computational methods assisting drug discovery and development are routine in the pharmaceutical industry. Digital recording of ADMET assays has provided a rich source of data for development of predictive models. Despite the accumulation of data and the public availability of advanced modeling algorithms, the utility of prediction in ADMET research is not clear. Here, we present a critical evaluation of the relationships between data volume, modeling algorithm, chemical representation and grouping, and temporal aspect (time sequence of assays) using an in-house ADMET database. We find no large difference in prediction algorithms nor any systemic and substantial gain from increasingly large datasets. Temporal-based data enlargement led to performance improvement in only in a limited number of assays, and with fractional improvement at best. Assays that are well-, intermediately-, or poorly-suited for ADMET predictions and reasons for such behavior are systematically identified, generating realistic expectations for areas in which computational models can be used to guide decision making in molecular design and development.

Keywords: ADMET modelling; algorithm comparison; chemical representation; congeneric series; machine learning.