Binding Mode Matters: Hotspot-Aware Drug Discovery via Explorative Preferences

arXiv:2611.14956v1 Announce Type: new
Abstract: Discovering hit molecules requires not just high binding affinity, but also the identification of diverse binding modes, which are critical for experimental assays. Existing generative approaches have predominantly relied on optimizing a scalar docking score, obscuring the distinct contributions of key binding determinants. To this end, we introduce a paradigm shift by formulating target-based drug design as a multi-objective exploration task, where each objective explicitly corresponds to enhancing interactions with a specific hotspot. Here, we introduce BindMol, a novel generative framework driven by a customized multi-objective reinforcement learning algorithm. By incorporating explorative preferences during training, our approach efficiently uncovers molecules with diverse and desirable binding profiles. Empirical results demonstrate that BindMol facilitates the discovery of high-affinity compounds characterized by both structural novelty and diverse binding modes. Validated across target-based drug discovery and multi-property optimization tasks, our approach provides a versatile paradigm for goal-oriented drug discovery.