Interpretable Drug–Target Prediction via Geometric Alignment: A Linear Alternative to Deep Architectural Complexity

Designing selective kinase inhibitors is a multiobjective optimization problem constrained by the structural conservation of the human kinome, along with the lack of high-quality interaction data. Traditional deep learning methods often train complex neural networks directly on small datasets and fail to generalize to new chemical scaffolds. To this end, we present Geometric Manifold Alignment, a novel linear approach that shifts away from architectural complexity. We introduce Multi-View Linear Manifold (MVLM), which aligns the latent spaces of ChemBERTa (small molecules) and ESM-2 (protein sequences) into a shared geometric interaction space. We pretrain MVLM on the Universal Foundation Set of 473 923 high-confidence interactions, where binding affinity is represented as geometric proximity between drug and target embeddings. Achieving an AUROC of 0.936 on KIBA and 0.928 on Davis, MVLM establishes the new state-of-the-art on industry-standard benchmarks, outperforming existing methods (p < 0.001). In this work, interpretability is geometric where interaction scores are cosine similarities in a shared manifold, and the learned structure recovers kinase phylogenetic relationships without supervision. We also demonstrate the model's utility as a transparent discovery engine by retrieving known clinical targets of FDA-approved drugs. Our findings suggest that aligning pretrained chemical and biological representations provides a scalable and interpretable approach to advancing computational drug discovery.