Tianfan Fu

Xuan Zhang, Limei Wang, Jacob Helwig et al. · cambridge, mit

Advances in artificial intelligence (AI) are fueling a new paradigm of discoveries in natural sciences. Today, AI has started to advance natural sciences by improving, accelerating, and enabling our understanding of natural phenomena at a wide range of spatial and temporal scales, giving rise to a new area of research known as AI for science (AI4Science). Being an emerging research paradigm, AI4Science is unique in that it is an enormous and highly interdisciplinary area. Thus, a unified and technical treatment of this field is needed yet challenging. This work aims to provide a technically thorough account of a subarea of AI4Science; namely, AI for quantum, atomistic, and continuum systems. These areas aim at understanding the physical world from the subatomic (wavefunctions and electron density), atomic (molecules, proteins, materials, and interactions), to macro (fluids, climate, and subsurface) scales and form an important subarea of AI4Science. A unique advantage of focusing on these areas is that they largely share a common set of challenges, thereby allowing a unified and foundational treatment. A key common challenge is how to capture physics first principles, especially symmetries, in natural systems by deep learning methods. We provide an in-depth yet intuitive account of techniques to achieve equivariance to symmetry transformations. We also discuss other common technical challenges, including explainability, out-of-distribution generalization, knowledge transfer with foundation and large language models, and uncertainty quantification. To facilitate learning and education, we provide categorized lists of resources that we found to be useful. We strive to be thorough and unified and hope this initial effort may trigger more community interests and efforts to further advance AI4Science.

Tianfan Fu, Wenhao Gao, Connor W. Coley et al.

Structure-based drug design (SBDD) aims to discover drug candidates by finding molecules (ligands) that bind tightly to a disease-related protein (targets), which is the primary approach to computer-aided drug discovery. Recently, applying deep generative models for three-dimensional (3D) molecular design conditioned on protein pockets to solve SBDD has attracted much attention, but their formulation as probabilistic modeling often leads to unsatisfactory optimization performance. On the other hand, traditional combinatorial optimization methods such as genetic algorithms (GA) have demonstrated state-of-the-art performance in various molecular optimization tasks. However, they do not utilize protein target structure to inform design steps but rely on a random-walk-like exploration, which leads to unstable performance and no knowledge transfer between different tasks despite the similar binding physics. To achieve a more stable and efficient SBDD, we propose Reinforced Genetic Algorithm (RGA) that uses neural models to prioritize the profitable design steps and suppress random-walk behavior. The neural models take the 3D structure of the targets and ligands as inputs and are pre-trained using native complex structures to utilize the knowledge of the shared binding physics from different targets and then fine-tuned during optimization. We conduct thorough empirical studies on optimizing binding affinity to various disease targets and show that RGA outperforms the baselines in terms of docking scores and is more robust to random initializations. The ablation study also indicates that the training on different targets helps improve performance by leveraging the shared underlying physics of the binding processes. The code is available at https://github.com/futianfan/reinforced-genetic-algorithm.

Zifeng Wang, Brandon Theodorou, Tianfan Fu et al.

Clinical trials are conducted to test the effectiveness and safety of potential drugs in humans for regulatory approval. Machine learning (ML) has recently emerged as a new tool to assist in clinical trials. Despite this progress, there have been few efforts to document and benchmark ML4Trial algorithms available to the ML research community. Additionally, the accessibility to clinical trial-related datasets is limited, and there is a lack of well-defined clinical tasks to facilitate the development of new algorithms. To fill this gap, we have developed PyTrial that provides benchmarks and open-source implementations of a series of ML algorithms for clinical trial design and operations. In this paper, we thoroughly investigate 34 ML algorithms for clinical trials across 6 different tasks, including patient outcome prediction, trial site selection, trial outcome prediction, patient-trial matching, trial similarity search, and synthetic data generation. We have also collected and prepared 23 ML-ready datasets as well as their working examples in Jupyter Notebooks for quick implementation and testing. PyTrial defines each task through a simple four-step process: data loading, model specification, model training, and model evaluation, all achievable with just a few lines of code. Furthermore, our modular API architecture empowers practitioners to expand the framework to incorporate new algorithms and tasks effortlessly. The code is available at https://github.com/RyanWangZf/PyTrial.

Yuanqi Du, Tianfan Fu, Jimeng Sun et al.

Molecule design is a fundamental problem in molecular science and has critical applications in a variety of areas, such as drug discovery, material science, etc. However, due to the large searching space, it is impossible for human experts to enumerate and test all molecules in wet-lab experiments. Recently, with the rapid development of machine learning methods, especially generative methods, molecule design has achieved great progress by leveraging machine learning models to generate candidate molecules. In this paper, we systematically review the most relevant work in machine learning models for molecule design. We start with a brief review of the mainstream molecule featurization and representation methods (including 1D string, 2D graph, and 3D geometry) and general generative methods (deep generative and combinatorial optimization methods). Then we summarize all the existing molecule design problems into several venues according to the problem setup, including input, output types and goals. Finally, we conclude with the open challenges and point out future opportunities of machine learning models for molecule design in real-world applications.

Wanhao Liu, Jiaqing Xie, Qian Tan et al.

As multimodal language models play an increasingly important role in scientific research, materials science offers a critical testbed due to its interdisciplinary, multimodal, and application-driven nature. However, existing materials benchmarks mainly focus on property prediction, knowledge QA, or characterization understanding, leaving the broader reasoning process from materials knowledge to application underexplored. To fill this gap, we present OmniMatBench, a human-calibrated multimodal reasoning benchmark for materials science. OmniMatBench contains 3,171 expert-curated QA and calculation problems across 19 materials-science subfields, spanning fundamental materials knowledge, structural and engineering materials, materials processing and manufacturing, and functional and applied materials. We evaluate 13 open-source and closed-source MLLMs and find that the best model achieves only a 0.372 overall score, revealing a substantial gap in current materials-science reasoning. Further analysis shows strong variation across subfields, fixed reasoning heuristics, uneven materials knowledge, and limited high-level knowledge application under formula-, retrieval-, and code-assisted settings. OmniMatBench provides crucial insights into the capabilities and limitations of current MLLMs and establishes a foundation for reliable AI assistants in materials-science research.

Namkyeong Lee, Heewoong Noh, Gyoung S. Na et al.

Machine learning (ML) has seen promising developments in materials science, yet its efficacy largely depends on detailed crystal structural data, which are often complex and hard to obtain, limiting their applicability in real-world material synthesis processes. An alternative, using compositional descriptors, offers a simpler approach by indicating the elemental ratios of compounds without detailed structural insights. However, accurately representing materials solely with compositional descriptors presents challenges due to polymorphism, where a single composition can correspond to various structural arrangements, creating ambiguities in its representation. To this end, we introduce PCRL, a novel approach that employs probabilistic modeling of composition to capture the diverse polymorphs from available structural information. Extensive evaluations on sixteen datasets demonstrate the effectiveness of PCRL in learning compositional representation, and our analysis highlights its potential applicability of PCRL in material discovery. The source code for PCRL is available at https://github.com/Namkyeong/PCRL.

Sixue Xing, Haoyu He, Kerui Wu et al.

LLM-guided evolutionary search (Evolve systems) has reached state-of-the-art results on mathematical and combinatorial tasks, yet most existing systems report only the best of many runs and leave the run-to-run distribution undocumented. We ask how a fixed budget of LLM calls should be allocated, and how reliably a single run reaches the reported numbers. Sweeping the depth-breadth grid over five models and three tasks, we identify two empirical regularities: a fitness-compute envelope along which capability ordering largely collapses on effective FLOPs, and a bilinear depth-breadth fit with task-specific interaction; both are gated by model-task capability. Motivated by these regularities, we propose BaSE (Bandit-based Self-Evolving), a multi-armed bandit that allocates LLM calls across parallel trajectories. Without changing the model, prompt, or evaluator, BaSE improves mean fitness by 12.3% over the strongest island-protocol baseline across 8 (model, task) cells, with the largest gains on high-variance settings: a reliability gain from allocation alone.

Yingzhou Lu, Lulu Chen, Yuanyuan Zhang et al.

Machine learning heavily relies on data, but real-world applications often encounter various data-related issues. These include data of poor quality, insufficient data points leading to under-fitting of machine learning models, and difficulties in data access due to concerns surrounding privacy, safety, and regulations. In light of these challenges, the concept of synthetic data generation emerges as a promising alternative that allows for data sharing and utilization in ways that real-world data cannot facilitate. This paper presents a comprehensive systematic review of existing studies that employ machine learning models for the purpose of generating synthetic data. The review encompasses various perspectives, starting with the applications of synthetic data generation, spanning computer vision, speech, natural language processing, healthcare, and business domains. Additionally, it explores different machine learning methods, with particular emphasis on neural network architectures and deep generative models. The paper also addresses the crucial aspects of privacy and fairness concerns related to synthetic data generation. Furthermore, this study identifies the challenges and opportunities prevalent in this emerging field, shedding light on the potential avenues for future research. By delving into the intricacies of synthetic data generation, this paper aims to contribute to the advancement of knowledge and inspire further exploration in synthetic data generation.

Pengcheng Jiang, Cao Xiao, Tianfan Fu et al.

Molecular representation learning is vital for various downstream applications, including the analysis and prediction of molecular properties and side effects. While Graph Neural Networks (GNNs) have been a popular framework for modeling molecular data, they often struggle to capture the full complexity of molecular representations. In this paper, we introduce a novel method called GODE, which accounts for the dual-level structure inherent in molecules. Molecules possess an intrinsic graph structure and simultaneously function as nodes within a broader molecular knowledge graph. GODE integrates individual molecular graph representations with multi-domain biochemical data from knowledge graphs. By pre-training two GNNs on different graph structures and employing contrastive learning, GODE effectively fuses molecular structures with their corresponding knowledge graph substructures. This fusion yields a more robust and informative representation, enhancing molecular property predictions by leveraging both chemical and biological information. When fine-tuned across 11 chemical property tasks, our model significantly outperforms existing benchmarks, achieving an average ROC-AUC improvement of 12.7% for classification tasks and an average RMSE/MAE improvement of 34.4% for regression tasks. Notably, GODE surpasses the current leading model in property prediction, with advancements of 2.2% in classification and 7.2% in regression tasks.

Hejie Cui, Jiaying Lu, Ran Xu et al.

This comprehensive review aims to provide an overview of the current state of Healthcare Knowledge Graphs (HKGs), including their construction, utilization models, and applications across various healthcare and biomedical research domains. We thoroughly analyzed existing literature on HKGs, covering their construction methodologies, utilization techniques, and applications in basic science research, pharmaceutical research and development, clinical decision support, and public health. The review encompasses both model-free and model-based utilization approaches and the integration of HKGs with large language models (LLMs). We searched Google Scholar for relevant papers on HKGs and classified them into the following topics: HKG construction, HKG utilization, and their downstream applications in various domains. We also discussed their special challenges and the promise for future work. The review highlights the potential of HKGs to significantly impact biomedical research and clinical practice by integrating vast amounts of biomedical knowledge from multiple domains. The synergy between HKGs and LLMs offers promising opportunities for constructing more comprehensive knowledge graphs and improving the accuracy of healthcare applications. HKGs have emerged as a powerful tool for structuring medical knowledge, with broad applications across biomedical research, clinical decision-making, and public health. This survey serves as a roadmap for future research and development in the field of HKGs, highlighting the potential of combining knowledge graphs with advanced machine learning models for healthcare transformation.

Yoshitaka Inoue, Tianci Song, Xinling Wang et al.

Advancements in large language models (LLMs) allow them to address diverse questions using human-like interfaces. Still, limitations in their training prevent them from answering accurately in scenarios that could benefit from multiple perspectives. Multi-agent systems allow the resolution of questions to enhance result consistency and reliability. While drug-target interaction (DTI) prediction is important for drug discovery, existing approaches face challenges due to complex biological systems and the lack of interpretability needed for clinical applications. DrugAgent is a multi-agent LLM system for DTI prediction that combines multiple specialized perspectives with transparent reasoning. Our system adapts and extends existing multi-agent frameworks by (1) applying coordinator-based architecture to the DTI domain, (2) integrating domain-specific data sources, including ML predictions, knowledge graphs, and literature evidence, and (3) incorporating Chain-of-Thought (CoT) and ReAct (Reason+Act) frameworks for transparent DTI reasoning. We conducted comprehensive experiments using a kinase inhibitor dataset, where our multi-agent LLM method outperformed the non-reasoning multi-agent model (GPT-4o mini) by 45% in F1 score (0.514 vs 0.355). Through ablation studies, we demonstrated the contributions of each agent, with the AI agent being the most impactful, followed by the KG agent and search agent. Most importantly, our approach provides detailed, human-interpretable reasoning for each prediction by combining evidence from multiple sources - a critical feature for biomedical applications where understanding the rationale behind predictions is essential for clinical decision-making and regulatory compliance. Code is available at https://anonymous.4open.science/r/DrugAgent-B2EA.

Yanchao Li, Wanhao Liu, Ben Gao et al.

LLM agents now draw on growing skill libraries to handle complex tasks. However, injecting more skills does not always improve task completion and can even degrade it. Existing methods still treat skill injection as a static step, selecting skills with fixed criteria, fixing the budget in advance, and leaving descriptions unchanged. We argue that this static treatment can undermine the utility of skills, because which skills are exposed, how many are included, and how they are presented all affect downstream performance. We propose SkillsInjector, a two-stage adaptive method that jointly addresses these decisions. First, a context planner learns execution-grounded skill preferences and admits an adaptive number of skills for each task. A set-aware renderer then tailors how selected descriptions are presented relative to their co-injected neighbors. Across tau2-bench, SkillsBench, and ALFWorld, SkillsInjector achieves the highest score, improving over the strongest baseline by 3.9, 6.1, and 7.3 percentage points, respectively. Ablation studies show that skill selection, adaptive budgeting, and set-aware rendering each contribute to the gain. These results show that skill-augmented agents benefit from optimizing the injected context itself. Code will be released upon publication

Yidong Zhou, Jintai Chen, Jinglei Cheng et al.

Drug discovery is lengthy and expensive, with traditional computer-aided design facing limits. This paper examines integrating quantum computing across the drug development cycle to accelerate and enhance workflows and rigorous decision-making. It highlights quantum approaches for molecular simulation, drug-target interaction prediction, and optimizing clinical trials. Leveraging quantum capabilities could accelerate timelines and costs for bringing therapies to market, improving efficiency and ultimately benefiting public health.

Pengcheng Xu, Tao Feng, Tianfan Fu et al.

In this work, we introduce a method to fine-tune a Transformer-based generative model for molecular de novo design. Leveraging the superior sequence learning capacity of Transformers over Recurrent Neural Networks (RNNs), our model can generate molecular structures with desired properties effectively. In contrast to the traditional RNN-based models, our proposed method exhibits superior performance in generating compounds predicted to be active against various biological targets, capturing long-term dependencies in the molecular structure sequence. The model's efficacy is demonstrated across numerous tasks, including generating analogues to a query structure and producing compounds with particular attributes, outperforming the baseline RNN-based methods. Our approach can be used for scaffold hopping, library expansion starting from a single molecule, and generating compounds with high predicted activity against biological targets.

Bohao Xu, Yingzhou Lu, Chenhao Li et al.

In drug discovery, predicting the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of small-molecule drugs is critical for ensuring safety and efficacy. However, the process of accurately predicting these properties is often resource-intensive and requires extensive experimental data. To address this challenge, we propose SMILES-Mamba, a two-stage model that leverages both unlabeled and labeled data through a combination of self-supervised pretraining and fine-tuning strategies. The model first pre-trains on a large corpus of unlabeled SMILES strings to capture the underlying chemical structure and relationships, before being fine-tuned on smaller, labeled datasets specific to ADMET tasks. Our results demonstrate that SMILES-Mamba exhibits competitive performance across 22 ADMET datasets, achieving the highest score in 14 tasks, highlighting the potential of self-supervised learning in improving molecular property prediction. This approach not only enhances prediction accuracy but also reduces the dependence on large, labeled datasets, offering a promising direction for future research in drug discovery.

Wanghan Xu, Yuhao Zhou, Yifan Zhou et al.

Despite advances in scientific AI, a coherent framework for Scientific General Intelligence (SGI)-the ability to autonomously conceive, investigate, and reason across scientific domains-remains lacking. We present an operational SGI definition grounded in the Practical Inquiry Model (PIM: Deliberation, Conception, Action, Perception) and operationalize it via four scientist-aligned tasks: deep research, idea generation, dry/wet experiments, and experimental reasoning. SGI-Bench comprises over 1,000 expert-curated, cross-disciplinary samples inspired by Science's 125 Big Questions, enabling systematic evaluation of state-of-the-art LLMs. Results reveal gaps: low exact match (10--20%) in deep research despite step-level alignment; ideas lacking feasibility and detail; high code executability but low execution result accuracy in dry experiments; low sequence fidelity in wet protocols; and persistent multimodal comparative-reasoning challenges. We further introduce Test-Time Reinforcement Learning (TTRL), which optimizes retrieval-augmented novelty rewards at inference, enhancing hypothesis novelty without reference answer. Together, our PIM-grounded definition, workflow-centric benchmark, and empirical insights establish a foundation for AI systems that genuinely participate in scientific discovery.

Ling Yue, Sixue Xing, Yingzhou Lu et al.

The advancement of natural language processing (NLP) in biology hinges on models' ability to interpret intricate biomedical literature. Traditional models often struggle with the complex and domain-specific language in this field. In this paper, we present BioMamba, a pre-trained model specifically designed for biomedical text mining. BioMamba builds upon the Mamba architecture and is pre-trained on an extensive corpus of biomedical literature. Our empirical studies demonstrate that BioMamba significantly outperforms models like BioBERT and general-domain Mamba across various biomedical tasks. For instance, BioMamba achieves a 100 times reduction in perplexity and a 4 times reduction in cross-entropy loss on the BioASQ test set. We provide an overview of the model architecture, pre-training process, and fine-tuning techniques. Additionally, we release the code and trained model to facilitate further research.

Zefeng Lin, Zhihang Zhang, Weirong Zhu et al.

Designing enzymes with substrate-binding pockets is a critical challenge in protein engineering, as catalytic activity depends on the precise interaction between pockets and substrates. Currently, generative models dominate functional protein design but cannot model pocket-substrate interactions, which limits the generation of enzymes with precise catalytic environments. To address this issue, we propose EnzyPGM, a unified framework that jointly generates enzymes and substrate-binding pockets conditioned on functional priors and substrates, with a particular focus on learning accurate pocket-substrate interactions. At its core, EnzyPGM includes two main modules: a Residue-atom Bi-scale Attention (RBA) that jointly models intra-residue dependencies and fine-grained interactions between pocket residues and substrate atoms, and a Residue Function Fusion (RFF) that incorporates enzyme function priors into residue representations. Also, we curate EnzyPock, an enzyme-pocket dataset comprising 83,062 enzyme-substrate pairs across 1,036 four-level enzyme families. Extensive experiments demonstrate that EnzyPGM achieves state-of-the-art performance on EnzyPock. Notably, EnzyPGM reduces the average binding energy of 0.47 kcal/mol over EnzyGen, showing its superior performance on substrate-specific enzyme design. The code and dataset will be released later.

Bohao Xu, Yingzhou Lu, Yoshitaka Inoue et al.

Protein function prediction is a pivotal task in drug discovery, significantly impacting the development of effective and safe therapeutics. Traditional machine learning models often struggle with the complexity and variability inherent in predicting protein functions, necessitating more sophisticated approaches. In this work, we introduce Protein-Mamba, a novel two-stage model that leverages both self-supervised learning and fine-tuning to improve protein function prediction. The pre-training stage allows the model to capture general chemical structures and relationships from large, unlabeled datasets, while the fine-tuning stage refines these insights using specific labeled datasets, resulting in superior prediction performance. Our extensive experiments demonstrate that Protein-Mamba achieves competitive performance, compared with a couple of state-of-the-art methods across a range of protein function datasets. This model's ability to effectively utilize both unlabeled and labeled data highlights the potential of self-supervised learning in advancing protein function prediction and offers a promising direction for future research in drug discovery.

Dannong Wang, Jintai Chen, Zhiding Liang et al.

Synthesizable molecular design (also known as synthesizable molecular optimization) is a fundamental problem in drug discovery, and involves designing novel molecular structures to improve their properties according to drug-relevant oracle functions (i.e., objective) while ensuring synthetic feasibility. However, existing methods are mostly based on random search. To address this issue, in this paper, we introduce a novel approach using the reinforcement learning method with quantum-inspired simulated annealing policy neural network to navigate the vast discrete space of chemical structures intelligently. Specifically, we employ a deterministic REINFORCE algorithm using policy neural networks to output transitional probability to guide state transitions and local search using genetic algorithm to refine solutions to a local optimum within each iteration. Our methods are evaluated with the Practical Molecular Optimization (PMO) benchmark framework with a 10K query budget. We further showcase the competitive performance of our method by comparing it against the state-of-the-art genetic algorithms-based method.

Zhou Zhang, Hanqun Cao, Cheng Tan et al.

Accurate RNA structure modeling remains difficult because RNA backbones are highly flexible, non-canonical interactions are prevalent, and experimentally determined 3D structures are comparatively scarce. We introduce \emph{RiboSphere}, a framework that learns \emph{discrete} geometric representations of RNA by combining vector quantization with flow matching. Our design is motivated by the modular organization of RNA architecture: complex folds are composed from recurring structural motifs. RiboSphere uses a geometric transformer encoder to produce SE(3)-invariant (rotation/translation-invariant) features, which are discretized with finite scalar quantization (FSQ) into a finite vocabulary of latent codes. Conditioned on these discrete codes, a flow-matching decoder reconstructs atomic coordinates, enabling high-fidelity structure generation. We find that the learned code indices are enriched for specific RNA motifs, suggesting that the model captures motif-level compositional structure rather than acting as a purely compressive bottleneck. Across benchmarks, RiboSphere achieves strong performance in structure reconstruction (RMSD 1.25\,Å, TM-score 0.84), and its pretrained discrete representations transfer effectively to inverse folding and RNA--ligand binding prediction, with robust generalization in data-scarce regimes.

Yoshitaka Inoue, Hunmin Lee, Tianfan Fu et al.

A challenge in drug response prediction is result interpretation compared to established knowledge. drGT is a graph deep learning model that predicts sensitivity and aids in biomarker identification using attention coefficients (ACs). drGT leverages a heterogeneous graph composed of relationships drawn from drugs, genes, and cell line responses. The model is trained and evaluated using major benchmark datasets: Sanger GDSC, NCI60, and Broad CTRP, which cover a wide range of drugs and cancer cell lines. drGT demonstrates AUROC of up to 94.5% under random splitting, 84.4% for unseen drugs, and 70.6% for unseen cell lines, comparable to existing benchmark methods while also providing interpretability. Regarding interpretability, we review drug-gene co-occurrences by text-mining PubMed abstracts for high-coefficient genes mentioning particular drugs. Across 976 drugs from NCI60 with known drug-target interactions (DTIs), model predictions utilized both known DTIs (36.9%) as well as additional predictive associations, many supported by literature. In addition, we compare the drug-gene associations identified by drGT with those from an established DTI prediction model and find that 63.67% are supported by either PubMed literature or predictions from the DTI model. Further, we describe the utilization of ACs to identify affected biological processes by each drug via enrichment analyses, thereby enhancing biological interpretability. Code is available at https://github.com/sciluna/drGT.

Ling Yue, Sixue Xing, Jintai Chen et al.

Clinical trials need to recruit a sufficient number of volunteer patients to demonstrate the statistical power of the treatment (e.g., a new drug) in curing a certain disease. Clinical trial recruitment has a significant impact on trial success. Forecasting whether the recruitment process would be successful before we run the trial would save many resources and time. This paper develops a novel deep & cross network with large language model (LLM)-augmented text feature that learns semantic information from trial eligibility criteria and predicts enrollment success. The proposed method enables interpretability by understanding which sentence/word in eligibility criteria contributes heavily to prediction. We also demonstrate the empirical superiority of the proposed method (0.7002 PR-AUC) over a bunch of well-established machine learning methods. The code and curated dataset are publicly available at https://anonymous.4open.science/r/TrialEnroll-7E12.

Qian Tan, Dongzhan Zhou, Peng Xia et al.

Multimodal large language models (MLLMs) have made impressive progress in many applications in recent years. However, chemical MLLMs that can handle cross-modal understanding and generation remain underexplored. To fill this gap, we propose ChemMLLM, a unified chemical multimodal large language model for molecule understanding and generation. Also, we design five multimodal tasks across text, molecular SMILES strings, and image, and curate the datasets. We benchmark ChemMLLM against a range of general leading MLLMs and Chemical LLMs on these tasks. Experimental results show that ChemMLLM achieves superior performance across all evaluated tasks. For example, in molecule image optimization task, ChemMLLM outperforms the best baseline (GPT-4o) by 116.75\% (4.27 vs 1.97 property improvement). The code is publicly available at https://github.com/bbsbz/ChemMLLM.git.

Yize Jiang, Xinze Li, Yuanyuan Zhang et al.

Existing protein-ligand docking studies typically focus on the self-docking scenario, which is less practical in real applications. Moreover, some studies involve heavy frameworks requiring extensive training, posing challenges for convenient and efficient assessment of docking methods. To fill these gaps, we design PoseX, an open-source benchmark to evaluate both self-docking and cross-docking, enabling a practical and comprehensive assessment of algorithmic advances. Specifically, we curated a novel dataset comprising 718 entries for self-docking and 1,312 entries for cross-docking; second, we incorporated 23 docking methods in three methodological categories, including physics-based methods (e.g., Schrödinger Glide), AI docking methods (e.g., DiffDock) and AI co-folding methods (e.g., AlphaFold3); third, we developed a relaxation method for post-processing to minimize conformational energy and refine binding poses; fourth, we built a leaderboard to rank submitted models in real-time. We derived some key insights and conclusions from extensive experiments: (1) AI approaches have consistently outperformed physics-based methods in overall docking success rate. (2) Most intra- and intermolecular clashes of AI approaches can be greatly alleviated with relaxation, which means combining AI modeling with physics-based post-processing could achieve excellent performance. (3) AI co-folding methods exhibit ligand chirality issues, except for Boltz-1x, which introduced physics-inspired potentials to fix hallucinations, suggesting modeling on stereochemistry improves the structural plausibility markedly. (4) Specifying binding pockets significantly promotes docking performance, indicating that pocket information can be leveraged adequately, particularly for AI co-folding methods, in future modeling efforts. The code, dataset, and leaderboard are released at https://github.com/CataAI/PoseX.

Yingzhou Lu, Minjie Shen, Ling Yue et al.

The surge in high-throughput omics data has reshaped the landscape of biological research, underlining the need for powerful, user-friendly data analysis and interpretation tools. This paper presents GenoCraft, a web-based comprehensive software solution designed to handle the entire pipeline of omics data processing. GenoCraft offers a unified platform featuring advanced bioinformatics tools, covering all aspects of omics data analysis. It encompasses a range of functionalities, such as normalization, quality control, differential analysis, network analysis, pathway analysis, and diverse visualization techniques. This software makes state-of-the-art omics data analysis more accessible to a wider range of users. With GenoCraft, researchers and data scientists have access to an array of cutting-edge bioinformatics tools under a user-friendly interface, making it a valuable resource for managing and analyzing large-scale omics data. The API with an interactive web interface is publicly available at https://genocraft.stanford. edu/. We also release all the codes in https://github.com/futianfan/GenoCraft.

Chris Zhuang, Debadyuti Mukherjee, Yingzhou Lu et al.

Molecular discovery has brought great benefits to the chemical industry. Various molecule design techniques are developed to identify molecules with desirable properties. Traditional optimization methods, such as genetic algorithms, continue to achieve state-of-the-art results across multiple molecular design benchmarks. However, these techniques rely solely on random walk exploration, which hinders both the quality of the final solution and the convergence speed. To address this limitation, we propose a novel approach called Gradient Genetic Algorithm (Gradient GA), which incorporates gradient information from the objective function into genetic algorithms. Instead of random exploration, each proposed sample iteratively progresses toward an optimal solution by following the gradient direction. We achieve this by designing a differentiable objective function parameterized by a neural network and utilizing the Discrete Langevin Proposal to enable gradient guidance in discrete molecular spaces. Experimental results demonstrate that our method significantly improves both convergence speed and solution quality, outperforming cutting-edge techniques. For example, it achieves up to a 25% improvement in the top-10 score over the vanilla genetic algorithm. The code is publicly available at https://github.com/debadyuti23/GradientGA.

Peisong Zhang, Manqiang Peng, Yuxuan Wu et al.

Estimating individualized treatment effects from longitudinal observational data is central to data-driven medicine, yet existing methods face a fundamental limitation: reducing confounding bias often suppresses clinically informative heterogeneity, degrading patient-specific predictions. Here, we identify this tension as a bias-precision paradox in causal representation learning and introduce sampling-based maximum mean discrepancy (sMMD), a stochastic alignment strategy that replaces global adversarial balancing with subset-level matching. We instantiate this approach in a framework for counterfactual outcome prediction with attribution-grounded interpretability. Across two large-scale ICU cohorts (n = 27,783), our framework improves accuracy under distribution shift, reducing error by up to 11.5% and substantially increasing recall in high-risk tasks. Mechanistic analyses show that sMMD selectively preserves clinically decisive variables. In human-AI evaluation, our method outperforms clinicians-in-training and large language models, and improves clinician accuracy by 14.7% while reducing decision time, enabling interpretable, real-time clinical decision support.

Hanqun Cao, Hongrui Zhang, Junde Xu et al.

Protein language models (PLMs) have advanced computational protein science through large-scale pretraining and scalable architectures. In parallel, reinforcement learning (RL) has broadened exploration and enabled precise multi-objective optimization in protein design. Yet whether RL can push PLMs beyond their pretraining priors to uncover latent sequence-structure-function rules remains unclear. We address this by pairing RL with PLMs across four domains: antimicrobial peptide design, kinase variant optimization, antibody engineering, and inverse folding. Using diverse RL algorithms and model classes, we ask if RL improves sampling efficiency and, more importantly, if it reveals capabilities not captured by supervised learning. Across benchmarks, RL consistently boosts success rates and sample efficiency. Performance follows a three-factor interaction: task headroom, reward fidelity, and policy capacity jointly determine gains. When rewards are accurate and informative, policies have sufficient capacity, and tasks leave room beyond supervised baselines, improvements scale; when rewards are noisy or capacity is constrained, gains saturate despite exploration. This view yields practical guidance for RL in protein design: prioritize reward modeling and calibration before scaling policy size, match algorithm and regularization strength to task difficulty, and allocate capacity where marginal gains are largest. Implementation is available at https://github.com/chq1155/RL-PLM.

Sixue Xing, Xuanye Xia, Kerui Wu et al.

Clinical trial failure remains a central bottleneck in drug development, where minor protocol design flaws can irreversibly compromise outcomes despite promising therapeutics. Although cutting-edge AI methods achieve strong performance in predicting trial success, they are inherently reactive for merely diagnosing risk without offering actionable remedies once failure is anticipated. To fill this gap, this paper proposes ClinicalReTrial, a self-evolving AI agent framework that addresses this gap by casting clinical trial reasoning as an iterative protocol redesign problem. Our method integrates failure diagnosis, safety-aware modification, and candidate evaluation in a closed-loop, reward-driven optimization framework. Serving the outcome prediction model as a simulation environment, ClinicalReTrial enables low-cost evaluation of protocol modifications and provides dense reward signals for continuous self-improvement. To support efficient exploration, the framework maintains hierarchical memory that captures iteration-level feedback within trials and distills transferable redesign patterns across trials. Empirically, ClinicalReTrial improves 83.3% of trial protocols with a mean success probability gain of 5.7%, and retrospective case studies demonstrate strong alignment between the discovered redesign strategies and real-world clinical trial modifications.

Haoyu Zhou, Ping Xue, Hao Zhang et al.

Deploying 3D graph neural networks (GNNs) that are equivariant to 3D rotations (the group SO(3)) on edge devices is challenging due to their high computational cost. This paper addresses the problem by compressing and accelerating an SO(3)-equivariant GNN using low-bit quantization techniques. Specifically, we introduce three innovations for quantized equivariant transformers: (1) a magnitude-direction decoupled quantization scheme that separately quantizes the norm and orientation of equivariant (vector) features, (2) a branch-separated quantization-aware training strategy that treats invariant and equivariant feature channels differently in an attention-based $SO(3)$-GNN, and (3) a robustness-enhancing attention normalization mechanism that stabilizes low-precision attention computations. Experiments on the QM9 and rMD17 molecular benchmarks demonstrate that our 8-bit models achieve accuracy on energy and force predictions comparable to full-precision baselines with markedly improved efficiency. We also conduct ablation studies to quantify the contribution of each component to maintain accuracy and equivariance under quantization, using the Local error of equivariance (LEE) metric. The proposed techniques enable the deployment of symmetry-aware GNNs in practical chemistry applications with 2.37--2.73x faster inference and 4x smaller model size, without sacrificing accuracy or physical symmetry.

Shuaike Shen, Jiaqing Xie, Zhuo Yang et al.

Recent advances in molecular foundation models have shown impressive performance in molecular property prediction and de novo molecular design, with promising applications in areas such as drug discovery and reaction prediction. Nevertheless, most existing approaches rely exclusively on SMILES representations and overlook both experimental spectra and 3D structural information-two indispensable sources for capturing molecular behavior in real-world scenarios. This limitation reduces their effectiveness in tasks where stereochemistry, spatial conformation, and experimental validation are critical. To overcome these challenges, we propose MolSpectLLM, a molecular foundation model pretrained on Qwen2.5-7B that unifies experimental spectroscopy with molecular 3D structure. By explicitly modeling molecular spectra, MolSpectLLM achieves state-of-the-art performance on spectrum-related tasks, with an average accuracy of 0.53 across NMR, IR, and MS benchmarks. MolSpectLLM also shows strong performance on the spectra analysis task, obtaining 15.5% sequence accuracy and 41.7% token accuracy on Spectra-to-SMILES, substantially outperforming large general-purpose LLMs. More importantly, MolSpectLLM not only achieves strong performance on molecular elucidation tasks, but also generates accurate 3D molecular structures directly from SMILES or spectral inputs, bridging spectral analysis, molecular elucidation, and molecular design. Code are available at \href{https://github.com/Eurekashen/MolSpectLLM}{https://github.com/Eurekashen/MolSpectLLM}.

Jiaqing Xie, Weida Wang, Ben Gao et al.

Quantitative chemistry is central to modern chemical research, yet the ability of large language models (LLMs) to perform its rigorous, step-by-step calculations remains underexplored. To fill this blank, we propose QCBench, a Quantitative Chemistry oriented benchmark comprising 350 computational chemistry problems across 7 chemistry subfields, which contains analytical chemistry, bio/organic chemistry, general chemistry, inorganic chemistry, physical chemistry, polymer chemistry and quantum chemistry. To systematically evaluate the mathematical reasoning abilities of large language models (LLMs), they are categorized into three tiers: easy, medium, and difficult. Each problem, rooted in realistic chemical scenarios, is structured to prevent heuristic shortcuts and demand explicit numerical reasoning. QCBench enables fine-grained diagnosis of computational weaknesses, reveals model-specific limitations across difficulty levels, and lays the groundwork for future improvements such as domain-adaptive fine-tuning or multi-modal integration. Evaluations on 24 LLMs demonstrate a consistent performance degradation with increasing task complexity, highlighting the current gap between language fluency and scientific computation accuracy. Code for QCBench is available at https://github.com/jiaqingxie/QCBench.

Yoshitaka Inoue, Tianfan Fu, Augustin Luna

Explainability is necessary for many tasks in biomedical research. Recent explainability methods have focused on attention, gradient, and Shapley value. These do not handle data with strong associated prior knowledge and fail to constrain explainability results based on known relationships between predictive features. We propose GraphPINE, a graph neural network (GNN) architecture leveraging domain-specific prior knowledge to initialize node importance optimized during training for drug response prediction. Typically, a manual post-prediction step examines literature (i.e., prior knowledge) to understand returned predictive features. While node importance can be obtained for gradient and attention after prediction, node importance from these methods lacks complementary prior knowledge; GraphPINE seeks to overcome this limitation. GraphPINE differs from other GNN gating methods by utilizing an LSTM-like sequential format. We introduce an importance propagation layer that unifies 1) updates for feature matrix and node importance and 2) uses GNN-based graph propagation of feature values. This initialization and updating mechanism allows for informed feature learning and improved graph representation. We apply GraphPINE to cancer drug response prediction using drug screening and gene data collected for over 5,000 gene nodes included in a gene-gene graph with a drug-target interaction (DTI) graph for initial importance. The gene-gene graph and DTIs were obtained from curated sources and weighted by article count discussing relationships between drugs and genes. GraphPINE achieves a PR-AUC of 0.894 and ROC-AUC of 0.796 across 952 drugs. Code is available at https://anonymous.4open.science/r/GraphPINE-40DE.

Kangyu Zheng, Yingzhou Lu, Zaixi Zhang et al.

Currently, the field of structure-based drug design is dominated by three main types of algorithms: search-based algorithms, deep generative models, and reinforcement learning. While existing works have typically focused on comparing models within a single algorithmic category, cross-algorithm comparisons remain scarce. In this paper, to fill the gap, we establish a benchmark to evaluate the performance of sixteen models across these different algorithmic foundations by assessing the pharmaceutical properties of the generated molecules and their docking affinities with specified target proteins. We highlight the unique advantages of each algorithmic approach and offer recommendations for the design of future SBDD models. We emphasize that 1D/2D ligand-centric drug design methods can be used in SBDD by treating the docking function as a black-box oracle, which is typically neglected. The empirical results show that 1D/2D methods achieve competitive performance compared with 3D-based methods that use the 3D structure of the target protein explicitly. Also, AutoGrow4, a 2D molecular graph-based genetic algorithm, dominates SBDD in terms of optimization ability. The relevant code is available in https://github.com/zkysfls/2024-sbdd-benchmark.

Songtao Liu, Jinghui Chen, Tianfan Fu et al.

This paper introduces a min-max optimization formulation for the Graph Signal Denoising (GSD) problem. In this formulation, we first maximize the second term of GSD by introducing perturbations to the graph structure based on Laplacian distance and then minimize the overall loss of the GSD. By solving the min-max optimization problem, we derive a new variant of the Graph Diffusion Convolution (GDC) architecture, called Graph Adversarial Diffusion Convolution (GADC). GADC differs from GDC by incorporating an additional term that enhances robustness against adversarial attacks on the graph structure and noise in node features. Moreover, GADC improves the performance of GDC on heterophilic graphs. Extensive experiments demonstrate the effectiveness of GADC across various datasets. Code is available at https://github.com/SongtaoLiu0823/GADC.

Namkyeong Lee, Yunhak Oh, Heewoong Noh et al.

Molecular Relational Learning (MRL) is a rapidly growing field that focuses on understanding the interaction dynamics between molecules, which is crucial for applications ranging from catalyst engineering to drug discovery. Despite recent progress, earlier MRL approaches are limited to using only the 2D topological structure of molecules, as obtaining the 3D interaction geometry remains prohibitively expensive. This paper introduces a novel 3D geometric pre-training strategy for MRL (3DMRL) that incorporates a 3D virtual interaction environment, overcoming the limitations of costly traditional quantum mechanical calculation methods. With the constructed 3D virtual interaction environment, 3DMRL trains 2D MRL model to learn the global and local 3D geometric information of molecular interaction. Extensive experiments on various tasks using real-world datasets, including out-of-distribution and extrapolation scenarios, demonstrate the effectiveness of 3DMRL, showing up to a 24.93% improvement in performance across 40 tasks. Our code is publicly available at https://github.com/Namkyeong/3DMRL.

Tianfan Fu, Cao Xiao, Xinhao Li et al.

Molecule optimization is a fundamental task for accelerating drug discovery, with the goal of generating new valid molecules that maximize multiple drug properties while maintaining similarity to the input molecule. Existing generative models and reinforcement learning approaches made initial success, but still face difficulties in simultaneously optimizing multiple drug properties. To address such challenges, we propose the MultI-constraint MOlecule SAmpling (MIMOSA) approach, a sampling framework to use input molecule as an initial guess and sample molecules from the target distribution. MIMOSA first pretrains two property agnostic graph neural networks (GNNs) for molecule topology and substructure-type prediction, where a substructure can be either atom or single ring. For each iteration, MIMOSA uses the GNNs' prediction and employs three basic substructure operations (add, replace, delete) to generate new molecules and associated weights. The weights can encode multiple constraints including similarity and drug property constraints, upon which we select promising molecules for next iteration. MIMOSA enables flexible encoding of multiple property- and similarity-constraints and can efficiently generate new molecules that satisfy various property constraints and achieved up to 49.6% relative improvement over the best baseline in terms of success rate. The code repository (including readme file, data preprocessing and model construction, evaluation) is available https://github.com/futianfan/MIMOSA.

Peng Sun, Huawen Shen, Yi Ban et al.

Visual instruction tuning is crucial for improving vision-language large models (VLLMs). However, many samples can be solved via linguistic patterns or common-sense shortcuts, without genuine cross-modal reasoning, limiting the effectiveness of multimodal learning. Prior data selection methods often rely on costly proxy model training and focus on difficulty or diversity, failing to capture a sample's true contribution to vision-language joint reasoning. In this paper, we propose CVS, a training-free data selection method based on the insight that, for high-quality multimodal samples, introducing the question should substantially alter the model's assessment of answer validity given an image. CVS leverages a frozen VLLM as an evaluator and measures the discrepancy in answer validity with and without conditioning on the question, enabling the identification of samples that require vision-language joint reasoning while filtering semantic-conflict noise. Experiments on Vision-Flan and The Cauldron show that CVS achieves solid performance across datasets. On Vision-Flan, CVS outperforms full-data training by 3.5% and 4.8% using only 10% and 15% of the data, respectively, and remains robust on the highly heterogeneous Cauldron dataset. Moreover, CVS reduces computational cost by 17.3% and 44.4% compared to COINCIDE and XMAS.

Zhuo Yang, Yeyun Chen, Jiaqing Xie et al.

Molecular editing and optimization are multi-step problems that require iteratively improving properties while keeping molecules chemically valid and structurally similar. We frame both tasks as sequential, tool-guided decisions and introduce MolAct, an agentic reinforcement learning framework that employs a two-stage training paradigm: first building editing capability, then optimizing properties while reusing the learned editing behaviors. To the best of our knowledge, this is the first work to formalize molecular design as an Agentic Reinforcement Learning problem, where an LLM agent learns to interleave reasoning, tool-use, and molecular optimization. The framework enables agents to interact in multiple turns, invoking chemical tools for validity checking, property assessment, and similarity control, and leverages their feedback to refine subsequent edits. We instantiate the MolAct framework to train two model families: MolEditAgent for molecular editing tasks and MolOptAgent for molecular optimization tasks. In molecular editing, MolEditAgent-7B delivers 100, 95, and 98 valid add, delete, and substitute edits, outperforming strong closed "thinking" baselines such as DeepSeek-R1; MolEditAgent-3B approaches the performance of much larger open "thinking" models like Qwen3-32B-think. In molecular optimization, MolOptAgent-7B (trained on MolEditAgent-7B) surpasses the best closed "thinking" baseline (e.g., Claude 3.7) on LogP and remains competitive on solubility, while maintaining balanced performance across other objectives. These results highlight that treating molecular design as a multi-step, tool-augmented process is key to reliable and interpretable improvements.

Yue Wang, Tianfan Fu, Yinlong Xu et al.

Clinical trials are indispensable for medical research and the development of new treatments. However, clinical trials often involve thousands of participants and can span several years to complete, with a high probability of failure during the process. Recently, there has been a burgeoning interest in virtual clinical trials, which simulate real-world scenarios and hold the potential to significantly enhance patient safety, expedite development, reduce costs, and contribute to the broader scientific knowledge in healthcare. Existing research often focuses on leveraging electronic health records (EHRs) to support clinical trial outcome prediction. Yet, trained with limited clinical trial outcome data, existing approaches frequently struggle to perform accurate predictions. Some research has attempted to generate EHRs to augment model development but has fallen short in personalizing the generation for individual patient profiles. Recently, the emergence of large language models has illuminated new possibilities, as their embedded comprehensive clinical knowledge has proven beneficial in addressing medical issues. In this paper, we propose a large language model-based digital twin creation approach, called TWIN-GPT. TWIN-GPT can establish cross-dataset associations of medical information given limited data, generating unique personalized digital twins for different patients, thereby preserving individual patient characteristics. Comprehensive experiments show that using digital twins created by TWIN-GPT can boost the clinical trial outcome prediction, exceeding various previous prediction approaches.

Tianyi Chen, Yingzhou Lu, Nan Hao et al.

The importance of uncertainty quantification is increasingly recognized in the diverse field of machine learning. Accurately assessing model prediction uncertainty can help provide deeper understanding and confidence for researchers and practitioners. This is especially critical in medical diagnosis and drug discovery areas, where reliable predictions directly impact research quality and patient health. In this paper, we proposed incorporating uncertainty quantification into clinical trial outcome predictions. Our main goal is to enhance the model's ability to discern nuanced differences, thereby significantly improving its overall performance. We have adopted a selective classification approach to fulfill our objective, integrating it seamlessly with the Hierarchical Interaction Network (HINT), which is at the forefront of clinical trial prediction modeling. Selective classification, encompassing a spectrum of methods for uncertainty quantification, empowers the model to withhold decision-making in the face of samples marked by ambiguity or low confidence, thereby amplifying the accuracy of predictions for the instances it chooses to classify. A series of comprehensive experiments demonstrate that incorporating selective classification into clinical trial predictions markedly enhances the model's performance, as evidenced by significant upticks in pivotal metrics such as PR-AUC, F1, ROC-AUC, and overall accuracy. Specifically, the proposed method achieved 32.37\%, 21.43\%, and 13.27\% relative improvement on PR-AUC over the base model (HINT) in phase I, II, and III trial outcome prediction, respectively. When predicting phase III, our method reaches 0.9022 PR-AUC scores. These findings illustrate the robustness and prospective utility of this strategy within the area of clinical trial predictions, potentially setting a new benchmark in the field.

Ling Yue, Sixue Xing, Jintai Chen et al.

Large Language Models (LLMs) and multi-agent systems have shown impressive capabilities in natural language tasks but face challenges in clinical trial applications, primarily due to limited access to external knowledge. Recognizing the potential of advanced clinical trial tools that aggregate and predict based on the latest medical data, we propose an integrated solution to enhance their accessibility and utility. We introduce Clinical Agent System (ClinicalAgent), a clinical multi-agent system designed for clinical trial tasks, leveraging GPT-4, multi-agent architectures, LEAST-TO-MOST, and ReAct reasoning technology. This integration not only boosts LLM performance in clinical contexts but also introduces novel functionalities. The proposed method achieves competitive predictive performance in clinical trial outcome prediction (0.7908 PR-AUC), obtaining a 0.3326 improvement over the standard prompt Method. Publicly available code can be found at https://anonymous.4open.science/r/ClinicalAgent-6671.

Lincan Li, Jiaqi Li, Catherine Chen et al.

In recent years, large language models (LLMs) have been widely adopted in political science tasks such as election prediction, sentiment analysis, policy impact assessment, and misinformation detection. Meanwhile, the need to systematically understand how LLMs can further revolutionize the field also becomes urgent. In this work, we--a multidisciplinary team of researchers spanning computer science and political science--present the first principled framework termed Political-LLM to advance the comprehensive understanding of integrating LLMs into computational political science. Specifically, we first introduce a fundamental taxonomy classifying the existing explorations into two perspectives: political science and computational methodologies. In particular, from the political science perspective, we highlight the role of LLMs in automating predictive and generative tasks, simulating behavior dynamics, and improving causal inference through tools like counterfactual generation; from a computational perspective, we introduce advancements in data preparation, fine-tuning, and evaluation methods for LLMs that are tailored to political contexts. We identify key challenges and future directions, emphasizing the development of domain-specific datasets, addressing issues of bias and fairness, incorporating human expertise, and redefining evaluation criteria to align with the unique requirements of computational political science. Political-LLM seeks to serve as a guidebook for researchers to foster an informed, ethical, and impactful use of Artificial Intelligence in political science. Our online resource is available at: http://political-llm.org/.

Yuhao Zhou, Yiheng Wang, Xuming He et al.

Scientific discoveries increasingly rely on complex multimodal reasoning based on information-intensive scientific data and domain-specific expertise. Empowered by expert-level scientific benchmarks, scientific Multimodal Large Language Models (MLLMs) hold the potential to significantly enhance this discovery process in realistic workflows. However, current scientific benchmarks mostly focus on evaluating the knowledge understanding capabilities of MLLMs, leading to an inadequate assessment of their perception and reasoning abilities. To address this gap, we present the Scientists' First Exam (SFE) benchmark, designed to evaluate the scientific cognitive capacities of MLLMs through three interconnected levels: scientific signal perception, scientific attribute understanding, scientific comparative reasoning. Specifically, SFE comprises 830 expert-verified VQA pairs across three question types, spanning 66 multimodal tasks across five high-value disciplines. Extensive experiments reveal that current state-of-the-art GPT-o3 and InternVL-3 achieve only 34.08% and 26.52% on SFE, highlighting significant room for MLLMs to improve in scientific realms. We hope the insights obtained in SFE will facilitate further developments in AI-enhanced scientific discoveries.

Ling Yue, Jonathan Li, Sixue Xing et al.

The clinical trial process, a critical phase in drug development, is essential for developing new treatments. The primary goal of interventional clinical trials is to evaluate the safety and efficacy of drug-based treatments for specific diseases. However, these trials are often lengthy, labor-intensive, and expensive. The duration of a clinical trial significantly impacts overall costs, making efficient timeline management crucial for controlling budgets and ensuring the economic feasibility of research. To address this issue, We propose TrialDura, a machine learning-based method that estimates the duration of clinical trials using multimodal data, including disease names, drug molecules, trial phases, and eligibility criteria. Then, we encode them into Bio-BERT embeddings specifically tuned for biomedical contexts to provide a deeper and more relevant semantic understanding of clinical trial data. Finally, the model's hierarchical attention mechanism connects all of the embeddings to capture their interactions and predict clinical trial duration. Our proposed model demonstrated superior performance with a mean absolute error (MAE) of 1.04 years and a root mean square error (RMSE) of 1.39 years compared to the other models, indicating more accurate clinical trial duration prediction. Publicly available code can be found at: https://anonymous.4open.science/r/TrialDura-F196.

Wenhao Zheng, Liaoyaqi Wang, Dongshen Peng et al.

The clinical trial is a pivotal and costly process, often spanning multiple years and requiring substantial financial resources. Therefore, the development of clinical trial outcome prediction models aims to exclude drugs likely to fail and holds the potential for significant cost savings. Recent data-driven attempts leverage deep learning methods to integrate multimodal data for predicting clinical trial outcomes. However, these approaches rely on manually designed modal-specific encoders, which limits both the extensibility to adapt new modalities and the ability to discern similar information patterns across different modalities. To address these issues, we propose a multimodal mixture-of-experts (LIFTED) approach for clinical trial outcome prediction. Specifically, LIFTED unifies different modality data by transforming them into natural language descriptions. Then, LIFTED constructs unified noise-resilient encoders to extract information from modal-specific language descriptions. Subsequently, a sparse Mixture-of-Experts framework is employed to further refine the representations, enabling LIFTED to identify similar information patterns across different modalities and extract more consistent representations from those patterns using the same expert model. Finally, a mixture-of-experts module is further employed to dynamically integrate different modality representations for prediction, which gives LIFTED the ability to automatically weigh different modalities and pay more attention to critical information. The experiments demonstrate that LIFTED significantly enhances performance in predicting clinical trial outcomes across all three phases compared to the best baseline, showcasing the effectiveness of our proposed key components.

Ming Hu, Chenglong Ma, Wei Li et al. · pku

Scientific Large Language Models (Sci-LLMs) are transforming how knowledge is represented, integrated, and applied in scientific research, yet their progress is shaped by the complex nature of scientific data. This survey presents a comprehensive, data-centric synthesis that reframes the development of Sci-LLMs as a co-evolution between models and their underlying data substrate. We formulate a unified taxonomy of scientific data and a hierarchical model of scientific knowledge, emphasizing the multimodal, cross-scale, and domain-specific challenges that differentiate scientific corpora from general natural language processing datasets. We systematically review recent Sci-LLMs, from general-purpose foundations to specialized models across diverse scientific disciplines, alongside an extensive analysis of over 270 pre-/post-training datasets, showing why Sci-LLMs pose distinct demands -- heterogeneous, multi-scale, uncertainty-laden corpora that require representations preserving domain invariance and enabling cross-modal reasoning. On evaluation, we examine over 190 benchmark datasets and trace a shift from static exams toward process- and discovery-oriented assessments with advanced evaluation protocols. These data-centric analyses highlight persistent issues in scientific data development and discuss emerging solutions involving semi-automated annotation pipelines and expert validation. Finally, we outline a paradigm shift toward closed-loop systems where autonomous agents based on Sci-LLMs actively experiment, validate, and contribute to a living, evolving knowledge base. Collectively, this work provides a roadmap for building trustworthy, continually evolving artificial intelligence (AI) systems that function as a true partner in accelerating scientific discovery.

Xinze Li, Penglei Wang, Tianfan Fu et al.

Structure-based drug design (SBDD), which aims to generate molecules that can bind tightly to the target protein, is an essential problem in drug discovery, and previous approaches have achieved initial success. However, most existing methods still suffer from invalid local structure or unrealistic conformation issues, which are mainly due to the poor leaning of bond angles or torsional angles. To alleviate these problems, we propose AUTODIFF, a diffusion-based fragment-wise autoregressive generation model. Specifically, we design a novel molecule assembly strategy named conformal motif that preserves the conformation of local structures of molecules first, then we encode the interaction of the protein-ligand complex with an SE(3)-equivariant convolutional network and generate molecules motif-by-motif with diffusion modeling. In addition, we also improve the evaluation framework of SBDD by constraining the molecular weights of the generated molecules in the same range, together with some new metrics, which make the evaluation more fair and practical. Extensive experiments on CrossDocked2020 demonstrate that our approach outperforms the existing models in generating realistic molecules with valid structures and conformations while maintaining high binding affinity.

Xiangrui Liu, Yuanyuan Zhang, Qianyu Shang et al.

Foundation models, first introduced in 2021, refer to large-scale pretrained models (e.g., large language models (LLMs) and vision-language models (VLMs)) that learn from extensive unlabeled datasets through unsupervised methods, enabling them to excel in diverse downstream tasks. These models, like GPT, can be adapted to various applications such as question answering and visual understanding, outperforming task-specific AI models and earning their name due to broad applicability across fields. The development of biomedical foundation models marks a significant milestone in the use of artificial intelligence (AI) to understand complex biological phenomena and advance medical research and practice. This survey explores the potential of foundation models in diverse domains within biomedical fields, including computational biology, drug discovery and development, clinical informatics, medical imaging, and public health. The purpose of this survey is to inspire ongoing research in the application of foundation models to health science.