Abstract Motivation Deep generative models have transformed drug molecule generation. However, molecules exhibit complex hierarchical structures, requiring models to simultaneously balance macroscopic topological coherence and microscopic chemical self-consistency. Although autoregressive (AR) and discrete diffusion paradigms are highly complementary, integrating their advantages within a unified architecture remains severely limited by traditional “atom-by-atom” fine-grained modeling. Results We propose MARD-Mol, a hybrid AR-diffusion framework based on motif-inspired units. By elevating the representation granularity from atoms to motif-inspired units and introducing a dual-stream hierarchical attention mechanism, it couples inter-unit AR global scaffold planning with intra-unit discrete diffusion generation. To support goal-directed drug discovery, we reformulate property optimization into an iterative “diagnose-and-repair” process, enabling targeted optimization of defective motifs while preserving the global scaffold. Extensive experiments demonstrate that MARD-Mol achieves an 86.0% Quality score in de novo generation and exhibits superior performance in fragment-constrained and multi-objective optimization, establishing a new paradigm for high-quality drug design. Availability and implementation The source code and datasets used in this study are available at GitHub: https://github.com/CSUBioGroup/MARD-Mol.
Sizhe Zhang, G. Luo, Wei Fan et al.· Bioinformatics· 0 citations
Accurate prediction of drug-target affinities (DTA) is critical for drug discovery. However, this task remains a significant challenge due to the complexity of modeling interactions between small ligands and large targets. In this study, we propose a multi-modal deep learning framework (CrossSG-DTA) to predict drug-target affinity by integrating sequence semantics with graph structural information. We leverage ChemBERTa and ESM-2 to extract rich semantic features for drugs and targets, respectively. In addition, a modified Graph Convolutional Network (GCN) is utilized to simultaneously capture structural data. To effectively fuse these heterogeneous features, we design a new symmetric dual cross-attention fusion mechanism for drugs and targets. This mechanism enables the model to capture complex dependencies between global sequence representations and local topological structures. Subsequently, the fused drug and target features are concatenated and fed into a three-layer Multi-Layer Perceptron (MLP) to obtain the final binding affinity. Experimental results on the Davis and KIBA datasets demonstrate that CrossSG-DTA significantly outperforms state-of-the-art methods. Finally, a case study on a glaucoma-related target highlights the practical utility of our model as a powerful in silico tool for DTA tasks.
Wei Lan, Tian Huang, Guohang He et al.· IEEE journal of biomedical a...· 0 citations
The results demonstrate the effectiveness of integrating multi-scale and multi-modal representations with cross-scale alignment for protein–RNA affinity prediction, and suggest that M2-PRNet can highlight relevant RNA-binding regions and support preliminary discrimination between strong and weak binders when plausible complex structures are available.
Junkai Wang, G. Luo, Yun-Song Yang et al.· Bioinformatics· 0 citations
This work designs a biological prior-guided feature fusion framework that integrates pseudo-structural epitope knowledge and CDR-specific attention mechanisms via a mixture-of-experts architecture to effectively capture complex binding landscapes in antibody screening and drug residence time analysis.
G. Luo, Junkai Wang, Sizhe Zhang et al.· Bioinformatics· 0 citations