MolFORM: Multi-modal Flow Matching for Structure-Based Drug Design

Abstract

Structure-based drug design (SBDD) seeks to generate molecules that bind effectively to protein targets by leveraging their 3D structural information. While diffusion-based generative models have become the predominant approach for SBDD, alternative non-autoregressive frameworks remain relatively underexplored. In this work, we introduce MolFORM, a novel generative framework that jointly models discrete (atom types) and continuous (3D coordinates) molecular modalities using multi-flow matching. To further enhance generation quality, we incorporate a preference-guided fine-tuning stage based on Direct Preference Optimization (DPO), using Vina score as a reward signal. We propose a multi-modal flow DPO co-modeling strategy that simultaneously aligns discrete and continuous modalities, leading to consistent improvements across multiple evaluation metrics. The source code for MolFORM is publicly available at https://github.com/huang3170/MolForm.git.