Discovery of New HER2 Inhibitors via Computational Docking, Pharmacophore Modeling, and Machine Learning.

The human epidermal growth factor receptor 2 (HER2) is a critical oncogene implicated in the development of various aggressive cancers, particularly breast cancer. Discovering novel HER2 inhibitors is crucial for expanding therapeutic options for HER2-related malignancies. In this study, we present a computational workflow that focuses on generating pharmacophores derived from docked poses of a selected list of 15 diverse, potent HER2 inhibitors, utilizing flexible docking. The resulting pharmacophores, along with other physicochemical molecular descriptors, were then evaluated in a machine learning-quantitative structure-activity relationship (ML-QSAR) analysis against 1,272 HER2 inhibitors. Several machine learning methods were assessed, and a genetic function algorithm (GFA) was employed for feature selection. Ultimately, GFA combined with Bagging and J48Graft classifiers produced the best self-consistent and predictive models. These models highlighted the significance of two pharmacophores, Hypo_1 and Hypo_2, in distinguishing potent from less active inhibitors. The successful ML-QSAR models and their associated pharmacophores were used to screen the National Cancer Institute (NCI) database for novel HER2 inhibitors. Three promising anti-HER2 leads were identified, with the top-performing lead demonstrating an experimental anti-HER2 IC₅₀ value of 3.85 μM. Notably, the three inhibitors exhibited distinct chemical scaffolds compared to existing HER2 inhibitors, as indicated by principal component analysis.