Not All Unlabeled Data Are Equal: Unlabeled Data Selection for Semi-Supervised QSAR Modeling with Large Chemical Repositories

Abstract

Semi-supervised learning (SSL) is particularly attractive in domains where labels are expensive to obtain, while unlabeled examples are readily available. Quantitative Structure-Activity Relationship (QSAR) modeling, which predicts molecular biological activity from chemical structure, is one such domain. Obtaining activity measurements requires costly wet-lab experiments, resulting in small labeled datasets, while chemical repositories such as ChEMBL contain millions of unlabeled molecules. Despite this apparent suitability, the potential of large chemical databases to improve QSAR models via SSL remains largely unexplored. Furthermore, it is unclear how unlabeled data should be selected in realistic SSL settings with genuine unlabeled data. We conduct a systematic study of unlabeled-data selection using 10 QSAR datasets extracted from ChEMBL and a pool of more than 400,000 unlabeled molecules. To this end, we evaluate three established SSL algorithms (self-training, co-training, and label propagation) and formulate four unlabeled-data selection strategies based on random, nearest-neighbor, furthest-neighbor, and mixed sampling. Our results show that unlabeled data from large chemical repositories can improve QSAR models, with at least one SSL configuration outperforming the supervised baseline on each of the 10 datasets. Moreover, the most reliable improvements are generally achieved by selecting a relatively small number of chemically distant molecules. This suggests that the composition of the unlabeled set may be more important than its size, challenging the common premise that SSL necessitates an abundance of unlabeled data.