Geometric Deep Learning‐Based Drug Design Models for Small‐Molecule Drug Discovery

Abstract

Deep neural network (DNN)‐based in silico models show great promise in predicting the properties and bioactivities of novel compounds, including small molecules. Among traditional approaches, structure‐based drug design (SBDD) remains a fundamental approach for drug discovery using molecular docking, scoring functions, and molecular dynamics simulations. However, these approaches are often constrained by limited flexibility, resolution, and generalizability. Geometric deep learning (GDL) offers a transformative alternative by enabling models to learn directly from non‐Euclidean molecular representations, such as graphs, point clouds, and meshes, capturing critical 3D spatial relationships inherent to protein–ligand interactions. This review highlights the theoretical underpinnings and practical applications of GDL in small‐molecule drug discovery, focusing on tasks including binding affinity prediction, virtual screening, de novo molecule generation, pose prediction, ADMET profiling, and protein flexibility modeling. We explore key GDL architectures, graph neural networks, SE(3)‐equivariant networks, 3D convolutional neural networks, point cloud models, and geometric transformers, and assess their performance across various drug discovery benchmarks. The integration of geometry‐aware AI models with experimental and computational workflows was also highlighted for its potential to streamline hit‐to‐lead optimization and advance rational drug design. Despite remarkable progress, the field faces challenges including limited high‐quality 3D structural datasets, protein flexibility representation, and the interpretability of deep models. Addressing these issues through hybrid modeling approaches, multi‐resolution learning, and self‐supervised training could further elevate GDL's impact. Ultimately, GDL stands at the frontier of AI‐enhanced pharmaceutical innovation, offering unprecedented precision, efficiency, and insight in the pursuit of next‐generation therapeutics.