ForceFM: Enhancing Protein-Ligand Predictions through Force-Guided Flow Matching

Huanlei Guo, Song Liu, Bingyi Jing

Keywords: Molecular Docking; Flow Matching; Energy-Guided Sampling

TL;DR: Force-Guided Flow Matching for Molecular Docking

Abstract: Molecular docking is a fundamental technique in structure-based drug discovery, playing a critical role in predicting the binding poses of protein-ligand complexes. While traditional docking methods are generally reliable, they are often computationally expensive. Recent deep learning (DL) approaches have substantially accelerated docking and improved prediction accuracy; however, they frequently generate conformations that lack physical plausibility due to insufficient integration of physical priors. To deal with these challenges, we propose ForceFM, a novel force-guided model that integrates a force-guided network into the generation process, steering ligand poses toward low-energy, physically realistic conformations. Force guidance also halves inference cost compared with the unguided approaches. Importantly, replacing the guiding potential with diverse energy functions-including Vina, Glide, Gnina, and Confscore-preserves or improves performance, underscoring the method's generality and robustness. These results highlight ForceFM's ability to set new standards in docking accuracy and physical consistency, surpassing the limitations of previous methods. Code is available at \url{https://github.com/Guhuary/ForceFM}.

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

Submission Number: 14979