Drug Discovery

Template-based molecular generation offers a promising avenue for drug design by ensuring generated compounds are synthetically accessible through predefined reaction templates and building blocks. In this work, we tackle three core challenges in template-based GFlowNets: (1) minimizing synthesis cost, (2) scaling to large building block libraries, and (3) effectively utilizing small fragment sets. We propose **Recursive Cost Guidance**, a backward policy framework that employs auxiliary machine learning models to approximate synthesis cost and viability. This guidance steers generation toward low-cost synthesis pathways, significantly enhancing cost-efficiency, molecular diversity, and quality, especially when paired with an **Exploitation Penalty** that balances the trade-off between exploration and exploitation. To enhance performance in smaller building block libraries, we develop a **Dynamic Library** mechanism that reuses intermediate high-reward states to construct full synthesis trees. Our approach establishes state-of-the-art results in template-based molecular generation.

Structure-based drug design (SBDD), aiming to generate 3D molecules with high binding affinity toward target proteins, is a vital approach in novel drug discovery. Although recent generative models have shown great potential, they suffer from unstable probability dynamics and mismatch between generated molecule size and the protein pockets geometry, resulting in inconsistent quality and off-target effects. We propose PAFlow, a novel target-aware molecular generation model featuring prior interaction guidance and a learnable atom number predictor. PAFlow adopts the efficient flow matching framework to model the generation process and constructs a new form of conditional flow matching for discrete atom types. A protein–ligand interaction predictor is incorporated to guide the vector field toward higher-affinity regions during generation, while an atom number predictor based on protein pocket information is designed to better align generated molecule size with target geometry. Extensive experiments on the CrossDocked2020 benchmark show that PAFlow achieves a new state-of-the-art in binding affinity (up to -8.31 Avg. Vina Score), simultaneously maintains favorable molecular properties.

Designing protein sequences of both high fitness and novelty is a challenging task in data-efficient protein engineering. Exploration beyond wild-type neighborhoods often leads to biologically implausible sequences or relies on surrogate models that lose fidelity in novel regions. Here, we propose ProSpero, an active learning framework in which a frozen pre-trained generative model is guided by a surrogate updated from oracle feedback. By integrating fitness-relevant residue selection with biologically-constrained Sequential Monte Carlo sampling, our approach enables exploration beyond wild-type neighborhoods while preserving biological plausibility. We show that our framework remains effective even when the surrogate is misspecified. ProSpero consistently outperforms or matches existing methods across diverse protein engineering tasks, retrieving sequences of both high fitness and novelty.

In many scientific and engineering fields, where acquiring high-quality data is expensive—such as medical imaging, environmental monitoring, and remote sensing—strategic sampling of unobserved regions based on prior observations is crucial for maximizing discovery rates within a constrained budget. The rise of powerful generative models, such as diffusion models, has enabled active target discovery in partially observable environments by leveraging learned priors—probabilistic representations that capture underlying structure from data. With guidance from sequentially gathered task-specific observations, these models can progressively refine exploration and efficiently direct queries toward promising regions. However, in domains where learning a strong prior is infeasible due to extremely limited data or high sampling cost (such as rare species discovery, diagnostics for emerging diseases, etc.), these methods struggle to generalize. To overcome this limitation, we propose a novel approach that enables effective active target discovery even in settings with uninformative priors, ensuring robust exploration and adaptability in complex real-world scenarios. Our framework is theoretically principled and draws inspiration from neuroscience to guide its design. Unlike black-box policies, our approach is inherently interpretable, providing clear insights into decision-making. Furthermore, it guarantees a strong, monotonic improvement in prior estimates with each new observation, leading to increasingly accurate sampling and reinforcing both reliability and adaptability in dynamic settings. Through comprehensive experiments and ablation studies across various domains, including species distribution modeling and remote sensing, we demonstrate that our method substantially outperforms baseline approaches.

Novelty detection in large scientific datasets faces two key challenges: the noisy and high-dimensional nature of experimental data, and the necessity of making *statistically robust* statements about any observed outliers. While there is a wealth of literature on anomaly detection via dimensionality reduction, most methods do not produce outputs compatible with quantifiable claims of scientific discovery. In this work we directly address these challenges, presenting the first step towards a unified pipeline for novelty detection adapted for the rigorous statistical demands of science. We introduce AutoSciDACT (Automated Scientific Discovery with Anomalous Contrastive Testing), a general-purpose pipeline for detecting novelty in scientific data. AutoSciDACT begins by creating expressive low-dimensional data representations using a contrastive pre-training, leveraging the abundance of high-quality simulated data in many scientific domains alongside expertise that can guide principled data augmentation strategies. These compact embeddings then enable an extremely sensitive machine learning-based two-sample test using the New Physics Learning Machine (NPLM) framework, which identifies and statistically quantifies deviations in observed data relative to a reference distribution (null hypothesis). We perform experiments across a range of astronomical, physical, biological, image, and synthetic datasets, demonstrating strong sensitivity to small injections of anomalous data across all domains.

Generalized Category Discovery (GCD) aims to leverage labeled samples from known categories to cluster unlabeled data that may include both known and unknown categories. While existing methods have achieved impressive results under standard conditions, their performance often deteriorates in the presence of distribution shifts. In this paper, we explore a more realistic task: Domain-Shifted Generalized Category Discovery (DS\_GCD), where the unlabeled data includes not only unknown categories but also samples from unknown domains. To tackle this challenge, we propose a \textbf{\underline{F}}requency-guided Gene\textbf{\underline{r}}alized Cat\textbf{\underline{e}}gory Discov\textbf{\underline{e}}ry framework (FREE) that enhances the model's ability to discover categories under distributional shift by leveraging frequency-domain information. Specifically, we first propose a frequency-based domain separation strategy that partitions samples into known and unknown domains by measuring their amplitude differences. We then propose two types of frequency-domain perturbation strategies: a cross-domain strategy, which adapts to new distributions by exchanging amplitude components across domains, and an intra-domain strategy, which enhances robustness to intra-domain variations within the unknown domain. Furthermore, we extend the self-supervised contrastive objective and semantic clustering loss to better guide the training process. Finally, we introduce a clustering-difficulty-aware resampling technique to adaptively focus on harder-to-cluster categories, further enhancing model performance. Extensive experiments demonstrate that our method effectively mitigates the impact of distributional shifts across various benchmark datasets and achieves superior performance in discovering both known and unknown categories.

We introduce **MLRC-Bench**, a benchmark designed to quantify how effectively language agents can tackle challenging **M**achine **L**earning (ML) **R**esearch **C**ompetitions, with a focus on open research problems that demand novel methodologies. Unlike prior work, e.g., AI Scientist, which evaluates the end-to-end agentic pipeline by using LLM-as-a-judge, MLRC-Bench measures the key steps of proposing and implementing novel research methods and evaluates them with rigorous protocol and objective metrics. Our curated suite of 7 competition tasks reveals significant challenges for LLM agents. Even the best-performing tested agent (gemini-exp-1206 under MLAB) closes only 9.3% of the gap between baseline and top human participant scores. Furthermore, our analysis reveals a misalignment between the *LLM-judged* innovation and their *actual* performance on cutting-edge ML research problems. MLRC-Bench is a dynamic benchmark, which is designed to continually grow with new ML competitions to encourage rigorous and objective evaluations of AI’s research capabilities. Our leaderboard and code are publicly available at https://huggingface.co/spaces/launch/MLRC_Bench.

Accurately modeling the target-drug complex at atom level presents a significant challenge in the computer-aided drug design. Traditional methods that rely solely on rigid transformations often fail to capture the adaptive interactions between targets and drugs, particularly during substantial conformational changes in targets upon ligand binding, which becomes especially critical when learning target-drug interactions in drug design. Accurately modeling these changes is crucial for understanding target-drug interactions and improving drug efficacy. To address these challenges, we introduce DynaPhArM, an SE(3)-Equivariant Transformer model specifically designed to capture adaptive alterations occurring within target-drug interactions. DynaPhArM utilizes the cooperative scalar-vector representation, drug-specific embeddings, and a diffusion process to effectively model the evolving dynamics of interactions between targets and drugs. Furthermore, we integrate physical information and energetic principles that maintain essential geometric constraints, such as bond lengths, bond angles, van der Waals forces (vdW), within a multi-task learning (MTL) framework to enhance accuracy. Experimental results demonstrate that DynaPhArM achieves state-of-the-art performance with an overall root mean square deviation (RMSD) of 2.01 Å and a sc-RMSD of 0.29 Å while exhibiting higher success rates compared to existing methodologies. Additionally, DynaPhArM shows promise in enhancing drug specificity, thereby simulating how targets adapt to various drugs through precise modeling of atomic-level interactions and conformational flexibility.

We study the problem of causal structure learning from a combination of observational and interventional data generated by a linear non-Gaussian structural equation model that might contain cycles. Recent results show that using mere observational data identifies the causal graph only up to a permutation-equivalence class. We obtain a combinatorial characterization of this class by showing that each equivalence class corresponds to a perfect matching in a bipartite graph. This bipartite representation allows us to analyze how interventions modify or constrain the matchings. Specifically, we show that each atomic intervention reveals one edge of the true matching and eliminates all incompatible causal graphs. Consequently, we formalize the optimal experiment design task as an adaptive stochastic optimization problem over the set of equivalence classes with a natural reward function that quantifies how many graphs are eliminated from the equivalence class by an intervention. We show that this reward function is adaptive submodular and provide a greedy policy with a provable near-optimal performance guarantee. A key technical challenge is to efficiently estimate the reward function without having to explicitly enumerate all the graphs in the equivalence class. We propose a sampling-based estimator using random matchings and analyze its bias and concentration behavior. Our simulation results show that performing a small number of interventions guided by our stochastic optimization framework recovers the true underlying causal structure.

Uncovering cause-and-effect mechanisms from data is fundamental to scientific progress. While large language models (LLMs) show promise for enhancing causal discovery (CD) from unstructured data, their application to the increasingly prevalent multimodal setting remains a critical challenge. Even with the advent of multimodal LLMs (MLLMs), their efficacy in multimodal CD is hindered by two primary limitations: (1) difficulty in exploring intra- and inter-modal interactions for comprehensive causal variable identification; and (2) insufficiency to handle structural ambiguities with purely observational data. To address these challenges, we propose MLLM-CD, a novel framework for multimodal causal discovery from unstructured data. It consists of three key components: (1) a novel contrastive factor discovery module to identify genuine multimodal factors based on the interactions explored from contrastive sample pairs; (2) a statistical causal structure discovery module to infer causal relationships among discovered factors; and (3) an iterative multimodal counterfactual reasoning module to refine the discovery outcomes iteratively by incorporating the world knowledge and reasoning capabilities of MLLMs. Extensive experiments on both synthetic and real-world datasets demonstrate the effectiveness of the proposed MLLM-CD in revealing genuine factors and causal relationships among them from multimodal unstructured data. The implementation code and data are available at https://github.com/JinLi-i/MLLM-CD.

AI-driven discovery can greatly reduce design time and enhance new therapeutics' effectiveness. Models using simulators explore broad design spaces but risk violating implicit constraints due to a lack of experimental priors. For example, in a new analysis across diverse models on the GuacaMol benchmark using supervised classifiers, over 60\% of molecules proposed had a high probability of being mutagenic. In this work, we introduce Medex, a dataset of priors for design problems extracted from literature describing compounds used in lab settings. It is constructed with LLM pipelines for discovering therapeutic entities in relevant paragraphs and summarizing information in concise fair-use facts. Medex consists of 32.3 million pairs of natural language facts, and appropriate entity representations (i.e. SMILES or RefSeq IDs). To demonstrate the potential of the data, we train LLM, CLIP, and LLaVA architectures to reason jointly about text and design targets and evaluate on tasks from the Therapeutic Data Commons (TDC). Medex is highly effective for creating models with strong priors: in supervised prediction problems that use our data for pretraining, our best models with 15M learnable parameters outperform larger 2B TxGemma on both regression and classification TDC tasks, and perform comparably to 9B models on average. Models built with Medex can be used as constraints while optimizing for novel molecules in GuacaMol, resulting in proposals that are safer and nearly as effective. We release our dataset on HuggingFace at https://huggingface.co/datasets/DocAndDesign/Medex, and will provide expanded versions as the available literature grows.

Drug recommendation systems aim to identify optimal drug combinations for patient care, balancing therapeutic efficacy and safety. Advances in large-scale longitudinal EHRs have enabled learning-based approaches that leverage patient histories such as diagnoses, procedures, and previously prescribed drugs, to model complex patient-drug relationships. Yet, many existing solutions overlook standard clinical practices that favor certain drugs for specific conditions and fail to fully integrate the influence of molecular substructures on drug efficacy and safety. In response, we propose \textbf{SubRec}, a unified framework that integrates representation learning across both patient and drug spaces. Specifically, SubRec introduces a conditional information bottleneck to extract core drug substructures most relevant to patient conditions, thereby enhancing interpretability and clinical alignment. Meanwhile, an adaptive vector quantization mechanism is designed to generate patient–drug interaction patterns into a condition-aware codebook which reuses clinically meaningful patterns, reduces training overhead, and provides a controllable latent space for recommendation. Crucially, the synergy between condition-specific substructure learning and discrete patient prototypes allows SubRec to make accurate and personalized drug recommendations. Experimental results on the real-world MIMIC III and IV demonstrate our model's advantages. The source code is available at \href{https://anonymous.4open.science/r/DrugRecommendation-5173}{https://anonymous.4open.science/}.

Predicting the binding affinity of protein-ligand complexes plays a vital role in drug discovery. Unfortunately, progress has been hindered by the lack of large-scale and high-quality binding affinity labels. The widely used PDBbind dataset has fewer than 20K labeled complexes. Self-supervised learning, especially graph contrastive learning (GCL), provides a unique opportunity to break the barrier by pretraining graph neural network models based on vast unlabeled complexes and fine-tuning the models on much fewer labeled complexes. However, the problem faces unique challenges, including a lack of a comprehensive unlabeled dataset with well-defined positive/negative complex pairs and the need to design GCL algorithms that incorporate the unique characteristics of such data. To fill the gap, we propose DecoyDB, a large-scale, structure-aware dataset specifically designed for self-supervised GCL on protein–ligand complexes. DecoyDB consists of high-resolution ground truth complexes and diverse decoy structures with computationally generated binding poses that range from realistic to suboptimal. Each decoy is annotated with a Root Mean Square Deviation (RMSD) from the native pose. We further design a customized GCL framework to pretrain graph neural networks based on DecoyDB and fine-tune the models with labels from PDBbind. Extensive experiments confirm that models pretrained with DecoyDB achieve superior accuracy, sample efficiency, and generalizability.

Flexible docking, which predicts the binding conformations of both proteins and small molecules by modeling their structural flexibility, plays a vital role in structure-based drug design. Although recent generative approaches, particularly diffusion-based models, have shown promising results, they require iterative sampling to generate candidate structures and depend on separate scoring functions for pose selection. This leads to an inefficient pipeline that is difficult to scale in real-world drug discovery workflows. To overcome these challenges, we introduce FIGRDock, a fast and accurate flexible docking framework that understands complicated interactions between molecules and proteins with a regression-based approach. FIGRDock leverages initial docking poses from conventional tools to distill interaction-aware distance patterns, which serve as explicit structural conditions to directly guide the prediction of the final protein-ligand complex via a regression model. This one-shot inference paradigm enables rapid and precise pose prediction without reliance on multi-step sampling or external scoring stages. Experimental results show that FIGRDock achieves up to 100× faster inference than diffusion-based docking methods, while consistently surpassing them in accuracy across standard benchmarks. These results suggest that FIGRDock has the potential to offer a scalable and efficient solution for flexible docking, advancing the pace of structure-based drug discovery.

In various scientific and engineering domains, where data acquisition is costly—such as in medical imaging, environmental monitoring, or remote sensing—strategic sampling from unobserved regions, guided by prior observations, is essential to maximize target discovery within a limited sampling budget. In this work, we introduce Diffusion-guided Active Target Discovery (DiffATD), a novel method that leverages diffusion dynamics for active target discovery. DiffATD maintains a belief distribution over each unobserved state in the environment, using this distribution to dynamically balance exploration-exploitation. Exploration reduces uncertainty by sampling regions with the highest expected entropy, while exploitation targets areas with the highest likelihood of discovering the target, indicated by the belief distribution and an incrementally trained reward model designed to learn the characteristics of the target. DiffATD enables efficient target discovery in a partially observable environment within a fixed sampling budget, all without relying on any prior supervised training. Furthermore, DiffATD offers interpretability, unlike existing black-box policies that require extensive supervised training. Through extensive experiments and ablation studies across diverse domains, including medical imaging, species discovery and remote sensing, we show that DiffATD performs significantly better than baselines and competitively with supervised methods that operate under full environmental observability.

Graph classification has long assumed a closed-world setting, limiting its applicability to real-world scenarios where new categories often emerge. To address this limitation, we introduce Graph-Level Novel Category Discovery (GLNCD), a new task aimed at identifying unseen graph categories without supervision from novel classes. We first adapt classical Novel Category Discovery (NCD) methods for images to the graph domain and evaluate these baseline methods on four diverse graph datasets curated for the GLNCD task. Our analysis reveals that these methods suffer a notable performance degradation compared to their image-based counterparts, due to two key challenges: (1) insufficient utilization of structural information in graph self-supervised learning (SSL), and (2) ineffective pseudo-labeling strategies based on ranking statistics (RS) that neglect graph structure. To alleviate these issues, we propose ProtoFGW-NCD, a framework consisting of two core components: ProtoFGW-CL, a novel graph SSL framework, and FGW-RS, a structure-aware pseudo-labeling method. Both components employ a differentiable Fused Gromov-Wasserstein (FGW) distance to effectively compare graphs by incorporating structural information. These components are built upon learnable prototype graphs, which enable efficient, parallel FGW-based graph comparisons and capture representative patterns within graph datasets. Experiments on four GLNCD benchmark datasets demonstrate the effectiveness of ProtoFGW-NCD.

Molecular docking is a fundamental technique in structure-based drug discovery, playing a critical role in predicting the binding poses of protein-ligand complexes. While traditional docking methods are generally reliable, they are often computationally expensive. Recent deep learning (DL) approaches have substantially accelerated docking and improved prediction accuracy; however, they frequently generate conformations that lack physical plausibility due to insufficient integration of physical priors. To deal with these challenges, we propose ForceFM, a novel force-guided model that integrates a force-guided network into the generation process, steering ligand poses toward low-energy, physically realistic conformations. Force guidance also halves inference cost compared with the unguided approaches. Importantly, replacing the guiding potential with diverse energy functions-including Vina, Glide, Gnina, and Confscore-preserves or improves performance, underscoring the method's generality and robustness. These results highlight ForceFM's ability to set new standards in docking accuracy and physical consistency, surpassing the limitations of previous methods. Code is available at \url{https://github.com/Guhuary/ForceFM}.

Causal discovery for dynamical systems poses a major challenge in fields where active interventions are infeasible. Most methods used to investigate these systems and their associated benchmarks are tailored to deterministic, low-dimensional and weakly nonlinear time-series data. To address these limitations, we present *CausalDynamics*, a large-scale benchmark and extensible data generation framework to advance the structural discovery of dynamical causal models. Our benchmark consists of true causal graphs derived from thousands of both linearly and nonlinearly coupled ordinary and stochastic differential equations as well as two idealized climate models. We perform a comprehensive evaluation of state-of-the-art causal discovery algorithms for graph reconstruction on systems with noisy, confounded, and lagged dynamics. *CausalDynamics* consists of a plug-and-play, build-your-own coupling workflow that enables the construction of a hierarchy of physical systems. We anticipate that our framework will facilitate the development of robust causal discovery algorithms that are broadly applicable across domains while addressing their unique challenges. We provide a user-friendly implementation and documentation on https://kausable.github.io/CausalDynamics.

Recent advances in Structure-based Drug Design (SBDD) have leveraged generative models for 3D molecular generation, predominantly evaluating model performance by binding affinity to target proteins. However, practical drug discovery necessitates high binding affinity along with synthetic feasibility and selectivity, critical properties that were largely neglected in previous evaluations. To address this gap, we identify fundamental limitations of conventional diffusion-based generative models in effectively guiding molecule generation toward these diverse pharmacological properties. We propose $\texttt{CByG}$, a novel framework extending Bayesian Flow Network into a gradient-based conditional generative model that robustly integrates property-specific guidance. Additionally, we introduce a comprehensive evaluation scheme incorporating practical benchmarks for binding affinity, synthetic feasibility, and selectivity, overcoming the limitations of conventional evaluation methods. Extensive experiments demonstrate that our proposed $\texttt{CByG}$, framework significantly outperforms baseline models across multiple essential evaluation criteria, highlighting its effectiveness and practicality for real-world drug discovery applications.

Real-world datasets are often a combination of unobserved subpopulations that follow distinct causal generating processes. In an observational study, for example, participants may fall into unknown groups that either (a) respond effectively to a drug, or (b) show no response due to drug resistance. Not accounting for such heterogeneity then risks biased estimates of drug effectiveness. In this work, we formulate this setting through a causal mixture model, in which the data-generating process of each variable depends on latent group membership (a or b). Specifically, we model each variable as a mixture of structural causal equation models, where latent categorical (mixing) variables index assignment to subpopulations. Unlike prior work, the approach allows for multiple independent mixing variables, each affecting distinct sets of observed variables. To infer both the graph, mixing variables, and assignments jointly, we integrate mixture modeling into score-based causal discovery; show theoretically that the resulting scoring criterion is consistent; and demonstrate empirically that the resulting causal discovery approach discovers the causal model in synthetic and real-world evaluations.