M²N: A Progressive Macro-to-Micro 3D Modeling Scheme for Unveiling Drug-Target Affinity

Abstract

Accurate drug-target affinity (DTA) prediction holds significant potential in the field of artificial intelligence (AI)-based drug discovery. However, existing methods primarily operate at a single scale, specifically at the macro (residue) scale for target proteins and the micro (atom) scale for drugs, which limits their ability to provide information at micro (atom) scale for targets and macro (functional group, FG) scale for drugs. This limitation hinders a comprehensive understanding of the binding patterns and properties of drug-target pairs. In this paper, we propose a progressive Macro-to-Micro 3D Modeling Network (M²N) that enables macro (residue/FG) to micro (atom) scale unified modeling, termed cross-scale, to predict DTA. Specifically, M²N operates drugs by learning their chemical properties and structural characteristics from a 3D FG graph to a 3D atom graph. Correspondingly, M²N encodes proteins from a 3D residue graph to a 3D atom graph to exploit their sequence, evolutionary, and geometric representations. Such cross-scale 3D modeling scheme allows for coarse-to-fine embedding optimization, followed by an adaptive fusion module to dynamically integrate the refined features by end-to-end learning. Extensive experiments on two datasets indicate that M²N not only outperforms state-of-the-art methods under various conditions, but also provides a new paradigm for target and drug unified modeling.