Controllable 3D Molecular Generation for Structure-Based Drug Design Through Bayesian Flow Networks and Gradient Integration

Seungyeon Choi, Hwanhee Kim, Chihyun Park, Dahyeon Lee, Seungyong Lee, Yoonju Kim, Hyoungjoon Park, Sein Kwon, Youngwan Jo, Sanghyun Park

Keywords: Structure-based Drug Design, 3D Molecule Generation, Generative Model

TL;DR: This study proposes a Bayesian Flow Network integrated with gradient-based guidance to generate molecules satisfying diverse properties.

Abstract: Recent advances in Structure-based Drug Design (SBDD) have leveraged generative models for 3D molecular generation, predominantly evaluating model performance by binding affinity to target proteins. However, practical drug discovery necessitates high binding affinity along with synthetic feasibility and selectivity, critical properties that were largely neglected in previous evaluations. To address this gap, we identify fundamental limitations of conventional diffusion-based generative models in effectively guiding molecule generation toward these diverse pharmacological properties. We propose $\texttt{CByG}$, a novel framework extending Bayesian Flow Network into a gradient-based conditional generative model that robustly integrates property-specific guidance. Additionally, we introduce a comprehensive evaluation scheme incorporating practical benchmarks for binding affinity, synthetic feasibility, and selectivity, overcoming the limitations of conventional evaluation methods. Extensive experiments demonstrate that our proposed $\texttt{CByG}$, framework significantly outperforms baseline models across multiple essential evaluation criteria, highlighting its effectiveness and practicality for real-world drug discovery applications.

Primary Area: Machine learning for sciences (e.g. climate, health, life sciences, physics, social sciences)

Submission Number: 19836