BoKDiff: Best-of-K Diffusion Alignment for Target-Specific 3D Molecule Generation

Abstract: Structure-based drug design (SBDD) leverages the 3D structure of biomolecular targets to guide the creation of new therapeutic agents. Recent advances in generative models, including diffusion models and geometric deep learning, have demonstrated promise in optimizing ligand generation. However, the scarcity of high-quality protein-ligand complex data and the inherent challenges in aligning generated ligands with target proteins limit the effectiveness of these methods. We propose BoKDiff, a novel framework that enhances ligand generation by combining multi-objective optimization and Best-of-K alignment methodologies. Built upon the DecompDiff model, BoKDiff generates diverse candidates and ranks them using a weighted evaluation of molecular properties such as QED, SA, and docking scores. To address alignment challenges, we introduce a method that relocates the center of mass of generated ligands to their docking poses, enabling accurate sub-component extraction. Additionally, we integrate a Best-of-N (BoN) sampling approach, which selects the optimal ligand from multiple generated candidates without requiring fine-tuning. BoN achieves exceptional results, with QED values exceeding 0.6, SA scores above 0.75, and a success rate surpassing 35%, demonstrating its efficiency and practicality. BoKDiff achieves state-of-the-art results on the CrossDocked2020 dataset, including a -8.58 average Vina docking score and a 26% success rate in molecule generation. This study is the first to apply Best-of-K alignment and Best-of-N sampling to SBDD, highlighting their potential to bridge generative modeling with practical drug discovery requirements. The code is provided at https://github.com/khodabandeh-ali/BoKDiff.git.