Structure-Based Drug Design (SBDD) has emerged as a popular approach in drug discovery, leveraging three-dimensional protein structures to generate drug ligands. However, existing generative models encounter several key challenges: (1) Incorporating boundary condition constraints, (2) Integrating hierarchical structural conditions and (3) Ensuring spatial modeling fidelity. To overcome these limitations, we propose SculptDrug, a spatial condition-aware generative model based on Bayesian Flow Networks (BFNs). First, SculptDrug follows a BFNs-based framework and employs a progressive denoising strategy to ensure spatial modeling fidelity, iteratively refining atom positions while enhancing local interactions for precise spatial alignment. Second, we introduce the Boundary Awareness Block, which incorporates protein surface constraints into the generative process to ensure that the generated ligands are geometrically compatible with the target protein. Finally, we design a Hierarchical Encoder that captures global structural context while preserving fine-grained molecular interactions, ensuring overall consistency and accurate ligand-protein conformations. We evaluate SculptDrug on the CrossDocked dataset, and experimental results demonstrate that SculptDrug outperforms state-of-the-art baselines, proving the efficacy of spatial condition-aware modeling.

Siyu Yan, Long Zeng, Xuecheng Wu, Chengcheng Han, Kongcheng Zhang, Chong Peng, Xuezhi Cao, Xunliang Cai, Chenjuan Guo. Proceedings of the 2025 Conference on Empirical Methods in Natural Language Processing. 2025.

Graph self-supervised learning has gained significant attention recently. However, many existing approaches heavily depend on perturbations, and inappropriate perturbations may corrupt the graph's inherent information. The Vector Quantized Variational Autoencoder (VQ-VAE) is a powerful autoencoder extensively used in fields such as computer vision; however, its application to graph data remains underexplored. In this paper, we provide an empirical analysis of vector quantization in the context of graph autoencoders, demonstrating its significant enhancement of the model's capacity to capture graph topology. Furthermore, we identify two key challenges associated with vector quantization when applying in graph data: codebook underutilization and codebook space sparsity. For the first challenge, we propose an annealing-based encoding strategy that promotes broad code utilization in the early stages of training, gradually shifting focus toward the most effective codes as training progresses. For the second challenge, we introduce a hierarchical two-layer codebook that captures relationships between embeddings through clustering. The second layer codebook links similar codes, encouraging the model to learn closer embeddings for nodes with similar features and structural topology in the graph. Our proposed model outperforms 16 representative baseline methods in self-supervised link prediction and node classification tasks across multiple datasets. Our implementation is available at https://github.com/vitaminzl/hqa-gae.