Molecular structure generation from mass spectrometry is fundamental for understanding cellular metabolism and discovering novel compounds. Although tandem mass spectrometry (MS/MS) enables the high-throughput acquisition of fragment fingerprints, these spectra often reflect higher-order interactions involving the concerted cleavage of multiple atoms and bonds-crucial for resolving complex isomers and non-local fragmentation mechanisms. However, most existing methods adopt atom-centric and pairwise interaction modeling, overlooking higher-order edge interactions and lacking the capacity to systematically capture essential many-body characteristics for structure generation. To overcome these limitations, we present MBGen, a Many-Body enhanced diffusion framework for de novo molecular structure Generation from mass spectra. By integrating a many-body attention mechanism and higher-order edge modeling, MBGen comprehensively leverages the rich structural information encoded in MS/MS spectra, enabling accurate de novo generation and isomer differentiation for novel molecules. Experimental results on the NPLIB1 and MassSpecGym benchmarks demonstrate that MBGen achieves superior performance, with improvements of up to 230% over state-of-the-art methods, highlighting the scientific value and practical utility of many-body modeling for mass spectrometry-based molecular generation. Further analysis and ablation studies show that our approach effectively captures higher-order interactions and exhibits enhanced sensitivity to complex isomeric and non-local fragmentation information.

Drug-drug interaction (DDI) prediction is pivotal for drug safety and clinical decision-making. Recently, subgraph-based methods utilizing knowledge graphs (KGs) and domain information have achieved promising results by extracting informative subgraphs for DDI prediction. However, existing subgraph extraction methods are typically coarse-grained and nonspecific, facing two key limitations: First, they are constrained by the vast and noisy nature of real-world KGs, making it challenging to identify the most informative substructures from the massive space of candidate subgraphs. Second, current methods often fail to exploit the molecular structural specificity of drugs to selectively extract relevant subgraphs, lacking effective integration of molecular structure information with knowledge graph context. To address these challenges, we propose RISE-DDI, a novel framework for Reinforced-based Informative Subgraph Extraction approach for drug-drug interaction prediction. Specifically, RISE-DDI formulates the subgraph extraction as a Markov Decision Process (MDP) and leverages a deep reinforcement learning (RL) agent to dynamically and adaptively extract the most informative and context-specific subgraphs for each drug pair. The agent is guided by a learnable structure-aware reward model that considers both the topological context from the knowledge graph and the molecular features of the drug pairs, thereby encouraging the selection of subgraphs that are both structurally relevant and biologically informative. Extensive experiments on DDI benchmark datasets demonstrate that our method outperforms state-of-the-art baselines in both transductive and inductive scenarios, achieving improvements of up to 20%. Furthermore, visualization analyses of the extracted subgraphs highlight the interpretability of our model, providing insights into the underlying mechanisms of drug interactions.

Protein design is revolutionizing biotechnology, yet existing approaches struggle to balance structural foldability with functional performance. Structure-based models excel at generating stable protein backbones but often overlook critical functional properties, while protein language models capture evolutionary and functional signals but frequently predict sequences lacking structural stability. Integrating these complementary approaches remains challenging due to their inherently conflicting objectives. We present MAProt, a multi-agent framework that synergistically combines structure-based and protein language model-based methods for protein design. Each agent specializes in a distinct aspect of the design objective: the structure-based agent (e.g., ProteinMPNN) ensures compatibility with the target backbone, while protein language model-based agents (e.g., ESM, SaProt) capture evolutionary plausibility and functional potential. To reconcile conflicts and achieve optimal trade-offs, we introduce a Pareto-based negotiation module that enables effective multi-objective coordination and consensus among agents. Extensive experiments on benchmark datasets demonstrate that MAProt achieves a remarkable improvement over state-of-the-art baselines, and generalizes robustly across a range of tasks, including thermodynamic folding stability design, functional protein design, and high-affinity antibody design. These results highlight the power of collaborative optimization for advancing rational protein engineering.

Diffusion-based molecular graph generative models have achieved significant success in template-free, single-step retrosynthesis prediction. However, these models typically generate reactants from scratch, often overlooking the fact that the scaffold of a product molecule typically remains unchanged during chemical reactions. To leverage this useful observation, we introduce a retrieval-augmented molecular graph generation framework. Our framework comprises three key components: a retrieval component that identifies similar molecules for the given product, an integration component that learns valuable clues from these molecules about which part of the product should remain unchanged, and a base generative model that is prompted by these clues to generate the corresponding reactants. We explore various design choices for critical and under-explored aspects of this framework and instantiate it as the Retrieval-Augmented RetroBridge (RARB). RARB demonstrates state-of-the-art performance on standard benchmarks, achieving a 14.8% relative improvement in top-1 accuracy over its base generative model, highlighting the effectiveness of retrieval augmentation. Additionally, RARB excels in handling out-of-distribution molecules, and its advantages remain significant even with smaller models or fewer denoising steps. These strengths make RARB highly valuable for real-world retrosynthesis applications, where extrapolation to novel molecules and high-throughput prediction are essential.

Phenotypic drug discovery presents a promising strategy for identifying first-in-class drugs by bypassing the need for specific drug targets. Recent advances in cell-based phenotypic screening tools, including Cell Painting and the LINCS L1000, provide essential cellular data that capture biological responses to compounds. While the integration of the multi-modal data enhances the use of contrastive learning (CL) methods for molecular phenotypic representation, these approaches treat all negative pairs equally, failing to discriminate molecules with similar phenotypes. To address these challenges, we introduce a foundational framework MINER that dynamically estimates the likelihoods of sample pairs as negative pairs based on uni-modal disentangled representations. In addition, our approach incorporates a mixture fusion strategy to effectively integrate multimodal data, even in cases where certain modalities are missing. Extensive experiments demonstrate that our method enhances both molecular property prediction and molecule-phenotype retrieval accuracy. Moreover, it successfully recommends drug candidates from phenotype for complex diseases documented in the literature. These findings underscore MINER’s potential to advance drug discovery by enabling deeper insights into disease mechanisms and improving drug candidate recommendations.

While Graph Neural Networks and Transformers have shown promise in predicting molecular properties, they struggle with directly modeling complex many-body interactions. Current methods often approximate interactions like three- and four-body terms in message passing, while attention-based models, despite enabling direct atom communication, are typically limited to triplets, making higher-order interactions computationally demanding. To address the limitations, we introduce MABNet, a geometric attention framework designed to model four-body interactions by facilitating direct communication among atomic quartets. This approach bypasses the computational bottlenecks associated with traditional triplet-based attention mechanisms, allowing for the efficient handling of higher-order interactions. MABNet achieves state-of-the-art performance on benchmarks like MD22 and SPICE. These improvements underscore its capability to accurately capture intricate many-body interactions in large molecules. By unifying rigorous many-body physics with computational efficiency, MABNet advances molecular simulations for applications in drug design and materials discovery, while its extensible framework paves the way for modeling higher-order quantum effects.

Graph Neural Networks (GNNs) have gained considerable traction for modeling molecular structures and predicting properties, but their interpretability remains a significant challenge in understanding chemical behaviors. Current interpretation methods often rely on post-hoc explanations, which aim to provide transparency in GNN decisions. However, these approaches struggle with interpreting complex subgraphs and fail to leverage explanations to enhance predictive capabilities. While transparent methods can enhance GNN predictions, they typically compromise on explanation precision. This limitation underscores the need for a new strategy that effectively integrates GNN explanations and predictions. In this study, we have developed a novel interpretable causal GNN framework that combines retrieval-based causal learning with Graph Information Bottleneck (GIB) theory. Our framework semi-parametrically identifies crucial subgraphs through GIB and compresses explanatory subgraphs using a causal module. The framework consistently outperformed state-of-the-art methods, achieving a 32.72% increase in precision for scientific explanation tasks involving diverse substructures. More importantly, the learned explanations were also shown to be able to improve GNN prediction performance. This advancement is particularly vital for molecular graph learning, as it addresses the critical need to interpret how molecular structures influence predicted properties, thereby aiding drug discovery and materials science by providing insights into chemical mechanisms.

Virtual Screening (VS) is vital for drug discovery but struggles with low hit rates and high computational costs. While Active Learning (AL) has shown promise in improving the efficiency of VS, traditional methods rely on inflexible and handcrafted heuristics, limiting adaptability in complex chemical spaces, particularly in balancing molecular diversity and selection accuracy. To overcome these challenges, we propose GLARE, a reinforced active learning framework that reformulates VS as a Markov Decision Process (MDP). Using Group Relative Policy Optimization (GRPO), GLARE dynamically balances chemical diversity, biological relevance, and computational constraints, eliminating the need for inflexible heuristics. Experiments show GLARE outperforms state-of-the-art AL methods, with a 64.8% average improvement in Enrichment Factors (EF). Additionally, GLARE enhances the performance of VS foundation models like DrugCLIP, achieving up to an 8-fold improvement in EF$_{0.5\\%}$ with as few as 15 active molecules. These results highlight the transformative potential of GLARE for adaptive and efficient drug discovery.

Ribonucleic acid (RNA) binds to molecules to achieve specific biological functions. While generative models are advancing biomolecule design, existing methods for designing RNA that target specific ligands face limitations in capturing RNA’s conformational flexibility, ensuring structural validity, and overcoming data scarcity. To address these challenges, we introduce RiboFlow, a synergistic flow matching model to co-design RNA structures and sequences based on target molecules. By integrating RNA backbone frames, torsion angles, and sequence features in an unified architecture, RiboFlow explicitly models RNA’s dynamic conformations while enforcing sequence-structure consistency to improve validity. Additionally, we curate RiboBind, a large-scale dataset of RNA-molecule interactions, to resolve the scarcity of high-quality structural data. Extensive experiments reveal that RiboFlow not only outperforms state-of-the-art RNA design methods by a large margin but also showcases controllable capabilities for achieving high binding affinity to target ligands. Our work bridges critical gaps in controllable RNA design, offering a framework for structure-aware, data-efficient generation.

Predicting changes in binding free energy ($\Delta\Delta G$) is essential for understanding protein-protein interactions, which are critical in drug design and protein engineering. However, existing methods often rely on pre-trained knowledge and heuristic features, limiting their ability to accurately model complex mutation effects, particularly higher-order and many-body interactions. To address these challenges, we propose H3-DDG, a Hypergraph-driven Hierarchical network to capture Higher-order many-body interactions across multiple scales. By introducing a hierarchical communication mechanism, H3-DDG effectively models both local and global mutational effects. Experimental results demonstrate state-of-the-art performance on multiple benchmarks. On the SKEMPI v2 dataset, H3-DDG achieves a Pearson correlation of 0.75, improving multi-point mutations prediction by 12.10%. On the challenging BindingGYM dataset, it outperforms Prompt-DDG and BA-DDG by 62.61% and 34.26%, respectively. Ablation and efficiency analyses demonstrate its robustness and scalability, while a case study on SARS-CoV-2 antibodies highlights its practical value in improving binding affinity for therapeutic design.

Lead optimization, aimed at improving binding affinity or other properties of hit compounds, is a crucial task in drug discovery. Though deep learning-based 3D generative models showed promise in enhancing the efficiency of de novo drug design recently, less research and attention has garnered for structure-based lead optimization. Herein, we propose a 3D pocket-aware diffusion model named Diffleop, which explicitly incorporates the knowledge of protein-ligand binding affinity and information on covalent bonds to guide the denoising sampling process for lead optimization with enhanced binding affinity and rational properties. Specifically, the bond constraint is achieved through diffusion on fully connected molecular graphs, and the determination of atom positions, atom and bond types in each sampling step is guided by the gradient of the binding affinity that is predicted through fitting with an E(3)-equivariant expert network. The comprehensive evaluations indicated that Diffleop outperforms baseline models on lead optimization with higher affinity and more binding interactions, and can generate more drug-like molecules with more rational structures. Diffleop was further applied to optimize 5-methyl-1H-imidazole, our newly discovered lead compound targeting human glutaminyl cyclases (QCs). Three synthesized compounds exhibit substantially improved inhibitory activities against QCs, with the most effective one showing an IC50 value of 8 nM and 3.5-fold better than clinical candidate PQ912.

Precise prediction of anti-cancer drug responses has become a crucial obstruction in anti-cancer drug design and clinical applications. In recent years, various deep learning methods have been applied to drug response prediction and become more accurate. However, they are still criticized as being non-transparent. To offer reliable drug response prediction in real-world applications, there is still a pressing demand to develop a model with high predictive performance as well as interpretability. In this study, we propose DrugVNN, an end-to-end interpretable drug response prediction framework, which extracts gene features of cell lines through a knowledge-guided visible neural network (VNN) and learns drug representation through a node-edge communicative message passing network (CMPNN). Additionally, between these two networks, a novel drug-aware gene attention gate is designed to direct the drug representation to VNN to simulate the effects of drugs. By evaluating on the GDSC dataset, DrugVNN achieved state-of-the-art performance. Moreover, DrugVNN can identify active genes and relevant signaling pathways for specific drug-cell line pairs with supporting evidence in the literature, implying the interpretability of our model.

With the recent progress in large-scale vision and language representation learning, Vision Language Pre-training (VLP) models have achieved promising improvements on various multi-modal downstream tasks. Albeit powerful, these models have not fully leveraged world knowledge to their advantage. A key challenge of knowledge-augmented VLP is the lack of clear connections between knowledge and multi-modal data. Moreover, not all knowledge present in images/texts is useful, therefore prior approaches often struggle to effectively integrate knowledge, visual, and textual information. In this study, we propose REtrieval-based knowledge Augmented Vision Language (REAVL), a novel knowledge-augmented pre-training framework to address the above issues. For the first time, we introduce a knowledge-aware self-supervised learning scheme that efficiently establishes the correspondence between knowledge and multi-modal data and identifies informative knowledge to improve the modeling of alignment and interactions between visual and textual modalities. By adaptively integrating informative knowledge with visual and textual information, REAVL achieves new state-of-the-art performance uniformly on knowledge-based vision-language understanding and multi-modal entity linking tasks, as well as competitive results on general vision-language tasks while only using 0.2% pre-training data of the best models. Our model shows strong sample efficiency and effective knowledge utilization.

Illuminating the interconnections between drugs and genes is an important topic in drug development and precision medicine. Currently, computational predictions of drug-gene interactions mainly focus on the binding interactions without considering other relation types like agonist, antagonist, etc. In addition, existing methods either heavily rely on high-quality domain features or are intrinsically transductive, which limits the capacity of models to generalize to drugs/genes that lack external information or are unseen during the training process. To address these problems, we propose a novel Communicative Subgraph representation learning for Multi-relational Inductive drug-Gene interactions prediction (CoSMIG), where the predictions of drug-gene relations are made through subgraph patterns, and thus are naturally inductive for unseen drugs/genes without retraining or utilizing external domain features. Moreover, the model strengthened the relations on the drug-gene graph through a communicative message passing mechanism. To evaluate our method, we compiled two new benchmark datasets from DrugBank and DGIdb. The comprehensive experiments on the two datasets showed that our method outperformed state-of-the-art baselines in the transductive scenarios and achieved superior performance in the inductive ones. Further experimental analysis including LINCS experimental validation and literature verification also demonstrated the value of our model.

Illuminating interactions between proteins and small drug molecules is a long-standing challenge in the field of drug discovery. Despite the importance of understanding these interactions, most previous works are limited by hand-designed scoring functions and insufficient conformation sampling. The recently-proposed graph neural network-based methods provides alternatives to predict protein-ligand complex conformation in a one-shot manner. However, these methods neglect the geometric constraints of the complex structure and weaken the role of local functional regions. As a result, they might produce unreasonable conformations for challenging targets and generalize poorly to novel proteins. In this paper, we propose Trigonometry-Aware Neural networKs for binding structure prediction, TANKBind, that builds trigonometry constraint as a vigorous inductive bias into the model and explicitly attends to all possible binding sites for each protein by segmenting the whole protein into functional blocks. We construct novel contrastive losses with local region negative sampling to jointly optimize the binding interaction and affinity. Extensive experiments show substantial performance gains in comparison to state-of-the-art physics-based and deep learning-based methods on commonly-used benchmark datasets for both binding structure and affinity predictions with variant settings.

Protein-DNA interactions play crucial roles in the biological systems, and identifying protein-DNA binding sites is the first step for mechanistic understanding of various biological activities (such as transcription and repair) and designing novel drugs. How to accurately identify DNA-binding residues from only protein sequence remains a challenging task. Currently, most existing sequence-based methods only consider contextual features of the sequential neighbors, which are limited to capture spatial information. Based on the recent breakthrough in protein structure prediction by AlphaFold2, we propose an accurate predictor, GraphSite, for identifying DNA-binding residues based on the structural models predicted by AlphaFold2. Here, we convert the binding site prediction problem into a graph node classification task and employ a transformer-based variant model to take the protein structural information into account. By leveraging predicted protein structures and graph transformer, GraphSite substantially improves over the latest sequence-based and structure-based methods. The algorithm is further confirmed on the independent test set of 181 proteins, where GraphSite surpasses the state-of-the-art structure-based method by 16.4% in area under the precision-recall curve and 11.2% in Matthews correlation coefficient, respectively. We provide the datasets, the predicted structures and the source codes along with the pre-trained models of GraphSite at https://github.com/biomed-AI/GraphSite. The GraphSite web server is freely available at https://biomed.nscc-gz.cn/apps/GraphSite.

Constructing appropriate representations of molecules lies at the core of numerous tasks such as material science, chemistry, and drug designs. Recent researches abstract molecules as attributed graphs and employ graph neural networks (GNN) for molecular representation learning, which have made remarkable achievements in molecular graph modeling. Albeit powerful, current models either are based on local aggregation operations and thus miss higher-order graph properties or focus on only node information without fully using the edge information. For this sake, we propose a Communicative Message Passing Transformer (CoMPT) neural network to improve the molecular graph representation by reinforcing message interactions between nodes and edges based on the Transformer architecture. Unlike the previous transformer-style GNNs that treat molecule as a fully connected graph, we introduce a message diffusion mechanism to leverage the graph connectivity inductive bias and reduce the message enrichment explosion. Extensive experiments demonstrated that the proposed model obtained superior performances (around 4% on average) against state-of-the-art baselines on seven chemical property datasets (graph-level tasks) and two chemical shift datasets (node-level tasks). Further visualization studies also indicated a better representation capacity achieved by our model.

Biomedical knowledge graphs (KGs), which can help with the understanding of complex biological systems and pathologies, have begun to play a critical role in medical practice and research. However, challenges remain in their embedding and use due to their complex nature and the specific demands of their construction. Existing studies often suffer from problems such as sparse and noisy datasets, insufficient modeling methods and non-uniform evaluation metrics. In this work, we established a comprehensive KG system for the biomedical field in an attempt to bridge the gap. Here, we introduced PharmKG, a multi-relational, attributed biomedical KG, composed of more than 500 000 individual interconnections between genes, drugs and diseases, with 29 relation types over a vocabulary of ~8000 disambiguated entities. Each entity in PharmKG is attached with heterogeneous, domain-specific information obtained from multi-omics data, i.e. gene expression, chemical structure and disease word embedding, while preserving the semantic and biomedical features. For baselines, we offered nine state-of-the-art KG embedding (KGE) approaches and a new biological, intuitive, graph neural network-based KGE method that uses a combination of both global network structure and heterogeneous domain features. Based on the proposed benchmark, we conducted extensive experiments to assess these KGE models using multiple evaluation metrics. Finally, we discussed our observations across various downstream biological tasks and provide insights and guidelines for how to use a KG in biomedicine. We hope that the unprecedented quality and diversity of PharmKG will lead to advances in biomedical KG construction, embedding and application.

Recent advances in single-cell RNA sequencing (scRNA-seq) technologies provide a great opportunity to study gene expression at cellular resolution, and the scRNA-seq data has been routinely conducted to unfold cell heterogeneity and diversity. A critical step for the scRNA-seq analyses is to cluster the same type of cells, and many methods have been developed for cell clustering. However, existing clustering methods are limited to extract the representations from expression data of individual cells, while ignoring the high-order structural relations between cells. Here, we proposed a new method (GraphSCC) to cluster cells based on scRNA-seq data by accounting structural relations between cells through a graph convolutional network. The representation learned from the graph convolutional network, together with another representation output from a denoising autoencoder network, are optimized by a dual self-supervised module for better cell clustering. Extensive experiments indicate that GraphSCC model outperforms state-of-the-art methods in various evaluation metrics on both simulated and real datasets.

MOTIVATION: RNA secondary structure plays a vital role in fundamental cellular processes, and identification of RNA secondary structure is a key step to understand RNA functions. Recently, a few experimental methods were developed to profile genome-wide RNA secondary structure, i.e. the pairing probability of each nucleotide, through high-throughput sequencing techniques. However, these high-throughput methods have low precision and cannot cover all nucleotides due to limited sequencing coverage. RESULTS: Here, we have developed a new method for the prediction of genome-wide RNA secondary structure profile from RNA sequence based on the extreme gradient boosting technique. The method achieves predictions with areas under the receiver operating characteristic curve (AUC) >0.9 on three different datasets, and AUC of 0.888 by another independent test on the recently released Zika virus data. These AUCs are consistently >5% greater than those by the CROSS method recently developed based on a shallow neural network. Further analysis on the 1000 Genome Project data showed that our predicted unpaired probabilities are highly correlated (>0.8) with the minor allele frequencies at synonymous, non-synonymous mutations, and mutations in untranslated regions, which were higher than those generated by RNAplfold. Moreover, the prediction over all human mRNA indicated a consistent result with previous observation that there is a periodic distribution of unpaired probability on codons. The accurate predictions by our method indicate that such model trained on genome-wide experimental data might be an alternative for analytical methods. AVAILABILITY AND IMPLEMENTATION: The GRASP is available for academic use at https://github.com/sysu-yanglab/GRASP. SUPPLEMENTARY INFORMATION: Supplementary data are available online.