Applicability Domain of Active Learning in Chemical Probe Identification: Convergence in Learning from Non-Specific Compounds and Decision Rule Clarification

Abstract

Efficient identification of chemical probes for the manipulation and understanding of biological systems demands specificity for target proteins. Computational means to optimize candidate compound selection for experimental selectivity evaluation are being sought. The active learning virtual screening method has demonstrated the ability to efficiently converge on predictive models with reduced datasets, though its applicability domain to probe identification has yet to be determined. In this article, we challenge active learning’s ability to predict inhibitory bioactivity profiles of selective compounds when learning from chemogenomic features found in non-selective ligand-target pairs. Comparison of controls versus multiple molecule representations de-convolutes factors contributing to predictive capability. Experiments using the matrix metalloproteinase family demonstrate maximum probe bioactivity prediction achieved from only approximately 20% of non-probe bioactivity; this data volume is consistent with prior chemogenomic active learning studies despite the increased difficulty from chemical biology experimental settings used here. Feature weight analyses are combined with a custom visualization to unambiguously detail how active learning arrives at classification decisions, yielding clarified expectations for chemogenomic modeling. The results influence tactical decisions for computational probe design and discovery.

Keywords

• chemical probes
• compound specificity
• ligand-target interactions
• chemogenomics
• active learning
• active projection
• decision tree
• molecular representation