药物发现

We study several problems in differentially private domain discovery, where each user holds a subset of items from a shared but unknown domain, and the goal is to output an informative subset of items. For set union, we show that the simple baseline Weighted Gaussian Mechanism (WGM) has a near-optimal $\ell_1$ missing mass guarantee on Zipfian data as well as a distribution-free $\ell_\infty$ missing mass guarantee. We then apply the WGM as a domain-discovery precursor for existing known-domain algorithms for private top-$k$ and $k$-hitting set and obtain new utility guarantees for their unknown domain variants. Finally, experiments demonstrate that all of our WGM-based methods are competitive with or outperform existing baselines for all three problems.

Designing 3D ligands that bind to a given protein pocket with high affinity is a fundamental task in Structure-Based Drug Design (SBDD). However, the lack of synthesizability of 3D ligands has been hindering progress toward experimental validation; moreover, computationally evaluating synthesizability is a non-trivial task. In this paper, we first benchmark eight classical synthesizability metrics across 11 SBDD methods. The comparison reveals significant inconsistencies between these metrics, making them impractical and inaccurate criteria for guiding SBDD methods toward synthesizable drug design. Therefore, we propose a simple yet effective SE(3)-invariant \textit{\underline{SYN}thesizability \underline{C}lassifier} (SYNC) to enable better synthesizability estimation in SBDD, which demonstrates superior generalizability and speed compared to existing metrics on five curated datasets. Finally, with SYNC as a plug-and-play module, we establish a synthesizability classifier-driven SBDD paradigm through guided diffusion and Direct Preference Optimization, where highly synthesizable molecules are directly generated without compromising binding affinity. Extensive experiments also demonstrate the effectiveness of SYNC and the advantage of our paradigm in synthesizable SBDD. Code is available at \url{https://anonymous.4open.science/r/SYNC-C94D/}.

Subcellular localization is a crucial biological task for drug target identification and function annotation. Although it has been biologically realized that subcellular localization is closely associated with protein structure, no existing dataset offers comprehensive 3D structural information with detailed subcellular localization annotations, thus severely hindering the application of promising structure-based models on this task. To address this gap, we introduce a new benchmark called $\textbf{CAPSUL}$, a $\textbf{C}$omprehensive hum$\textbf{A}$n $\textbf{P}$rotein benchmark for $\textbf{SU}$bcellular $\textbf{L}$ocalization. It features a dataset that integrates diverse 3D structural representations with fine-grained subcellular localization annotations carefully curated by domain experts. We evaluate this benchmark using a variety of state-of-the-art sequence-based and structure-based models, showcasing the importance of involving structural features in this task. Furthermore, we explore reweighting and single-label classification strategies to facilitate future investigation on structure-based methods for this task. Lastly, we showcase the powerful interpretability of structure-based methods through a case study on the Golgi apparatus, where we discover a decisive localization pattern $\alpha$-helix from attention mechanisms, demonstrating the potential for bridging the gap with intuitive biological interpretability and paving the way for data-driven discoveries in cell biology.

Fine-tuned Large Language Models (LLMs) encode rich task-specific features, but the form of these representations—especially within MLP layers—remains unclear. Empirical inspection of LoRA updates shows that new features concentrate in mid-layer MLPs, yet the scale of these layers obscures meaningful structure. Prior probing suggests that statistical priors may strengthen, split, or vanish across depth, motivating the need to study how neurons work together rather than in isolation. We introduce a mechanistic interpretability framework based on coalitional game theory, where neurons mimic agents in a hedonic game whose preferences capture their synergistic contributions to layer-local computations. Using top-responsive utilities and the PAC-Top-Cover algorithm, we extract stable coalitions of neurons—groups whose joint ablation has non-additive effects—and track their transitions across layers as persistence, splitting, merging, or disappearance. Applied to LLaMA, Mistral, and Pythia rerankers fine-tuned on scalar IR tasks, our method finds coalitions with consistently higher synergy than clustering baselines. By revealing how neurons cooperate to encode features, hedonic coalitions uncover higher-order structure beyond disentanglement and yield computational units that are functionally important, interpretable, and predictive across domains.

Small-molecule ligands extend protein functionality beyond natural amino acids, enabling sophisticated processes like catalysis, signal transduction, and light harvesting. However, designing proteins with high affinity and selectivity for arbitrary ligands remains a major challenge. We present Pallatom-Ligand, a diffusion model that performs end-to-end generation of ligand-binding proteins at atomic resolution. By directly learning the joint distribution of all atoms in the protein–ligand complexes, Pallatom-Ligand delivers state-of-the-art performance, achieving the highest *in silico* success rates in a comprehensive benchmark. In addition, Pallatom-Ligand's novel conditioning framework enables programmable control over global protein fold and atomic-level ligand solvent accessibility. With these capabilities, Pallatom-Ligand opens new opportunities for exploring the protein function space, advancing both generative modeling and computational protein engineering.

We introduce FragFM, a novel hierarchical framework via fragment-level discrete flow matching for efficient molecular graph generation. FragFM generates molecules at the fragment level, leveraging a coarse-to-fine autoencoder to reconstruct details at the atom level. Together with a stochastic fragment bag strategy to effectively handle an extensive fragment space, our framework enables more efficient and scalable molecular generation. We demonstrate that our fragment-based approach achieves better property control than the atom-based method and additional flexibility through conditioning the fragment bag. We also propose a Natural Product Generation benchmark (NPGen) to evaluate modern molecular graph generative models' ability to generate natural product-like molecules. Since natural products are biologically prevalidated and differ from typical drug-like molecules, our benchmark provides a more challenging yet meaningful evaluation relevant to drug discovery. We conduct a FragFM comparative study against various models on diverse molecular generation benchmarks, including NPGen, demonstrating superior performance. The results highlight the potential of fragment-based generative modeling for large-scale, property-aware molecular design, paving the way for more efficient exploration of chemical space.

Learning causal structures from temporal data is fundamental to many practical tasks, such as physical laws discovery and root causes localization. Real-world systems often exhibit long-term carry-over effects, where the value of a variable at the current time can be influenced by distant past values of other variables. These effects, due to their large temporal span, are challenging to observe or model. Existing methods typically consider finite lag orders, which may lead to confounding from early historical data. Moreover, incorporating historical information often results in computational scalability issues. In this paper, we establish a theoretical framework for causal discovery in complex temporal scenarios where observational data exhibit long-term carry-over effect, and propose LEVER, a theoretically guaranteed novel causal discovery method for incomplete temporal data. Specifically, based on the \textit{Limited-history Causal Identifiability Theorem}, we refine the variable values at each time step with data at a few preceding steps to mitigate long-term historical influences. Furthermore, we establish a theoretical connection between QR decomposition and causal discovery, and design an efficient reinforcement learning process to determine the optimal variable ordering. Finally, we recover the causal structure from the R matrix. We evaluate LEVER on both synthetic and real-world datasets. In static cases, LEVER reduces SHD by 17.29\%-40.00\% and improves the F1-score by 5.30\%-8.79\% compared to the best baseline. In temporal cases, it achieves a 64\% reduction in SHD and a 45\% improvement in F1-score. Additionally, LEVER demonstrates significantly higher precision on real-world data compared to baseline methods.

Accurate prediction of protein-ligand binding affinities remains a cornerstone problem in drug discovery. While binding affinity is inherently dictated by the 3D structure and dynamics of protein-ligand complexes, current deep learning approaches are limited by the lack of high-quality experimental structures with annotated binding affinities. To address this limitation, we introduce the Structurally Augmented IC50 Repository (SAIR), the largest publicly available dataset of protein-ligand 3D structures with associated activity data. The dataset comprises $5,244,285$ structures across $1,048,857$ unique protein-ligand systems, curated from the ChEMBL and BindingDB databases, which were then computationally folded using the Boltz-1x model. We provide a comprehensive characterization of the dataset, including distributional statistics of proteins and ligands, and evaluate the structural fidelity of the folded complexes using PoseBusters. Our analysis reveals that approximately $3 \%$ of structures exhibit physical anomalies, predominantly related to internal energy violations. As an initial demonstration, we benchmark several binding affinity prediction methods, including empirical scoring functions (Vina, Vinardo), a 3D convolutional neural network (Onionnet-2), and a graph neural network (AEV-PLIG). While machine learning-based models consistently outperform traditional scoring function methods, neither exhibit a high correlation with ground truth affinities, highlighting the need for models specifically fine-tuned to synthetic structure distributions. This work provides a foundation for developing and evaluating next-generation structure and binding-affinity prediction models and offers insights into the structural and physical underpinnings of protein-ligand interactions. The link to the data will be added upon publication, to preserve anonymity of the submission.

Generalized Category Discovery (GCD) seeks to discover categories by clustering unlabeled samples that mix known and novel classes. The prevailing recipe enforces compact clustering, this pursuit is largely blind to representation geometry: it over-compresses token manifolds, distorts eigen-structure, and yields brittle feature distributions that undermine discovery. We argue that GCD requires not more compression, but geometric restoration of an over-flattened feature space. Drawing inspiration from quantum information science, which similarly pursues representational completeness, we introduce Bures-Isotropy Alignment (BIA), which optimizes the class-token covariance toward an isotropic prior by minimizing the Bures distance. Under a mild trace constraint, BIA admits a practical surrogate equivalent to maximizing the nuclear norm of stacked class tokens, thereby promoting isotropic, non-collapsed subspaces without altering architectures. The induced isotropy homogenizes the eigen-spectrum and raises the von Neumann entropy of class-token autocorrelation, improving both cluster separability and class-number estimation. BIA is plug-and-play, implemented in a few lines on unlabeled batches, and consistently boosts strong GCD baselines on coarse- and fine-grained benchmarks, improving overall accuracy and reducing errors in the estimation of class-number. By restoring the geometry of token manifolds rather than compressing them blindly, BIA supplies compactness for known classes and cohesive emergence for novel ones, advancing robust open-world discovery.

We introduce ShinkaEvolve: a new framework leveraging large language models (LLMs) to advance scientific discovery with state-of-the-art performance and efficiency. The field of LLM-driven scientific discovery has seen significant progress, but has yet to overcome a critical limitation: sample inefficiency, requiring thousands of samples to identify effective solutions. ShinkaEvolve takes a concrete step towards addressing this critical limitation by introducing three key innovations: a parent sampling technique balancing exploration and exploitation, code novelty rejection-sampling for efficient search space exploration, and a bandit-based LLM ensemble selection strategy. When applied to the canonical circle-packing optimization task, ShinkaEvolve discovers a new state-of-the-art circle packing solution using only 150 samples, orders of magnitude fewer than prior frameworks. Furthermore, applied to a broader set of engineering problems, ShinkaEvolve designs robust agentic harnesses for AIME mathematical reasoning tasks, identifies improvements to ALE-Bench competitive programming solutions, and discovers novel mixture-of-expert load balancing loss functions to stabilize LLM training itself. We provide ShinkaEvolve's full code together with this submission, which will be open-sourced to accelerate open advancements to open-ended automated discovery across diverse computational problems.

Adversarial Imitation Learning (AIL) methods, while effective in settings with limited expert demonstrations, are often considered unstable. These approaches typically decompose into two components: Density Ratio (DR) estimation $\frac{\rho_E}{\rho_{\pi}}$, where a discriminator estimates the relative occupancy of state-action pairs under the policy versus the expert; and Reward Assignment (RA), where this ratio is transformed into a reward signal used to train the policy. While significant research has focused on improving density estimation, the role of reward assignment in influencing training dynamics and final policy performance has been largely overlooked. RA functions in AIL are typically derived from divergence minimization objectives, relying heavily on human design and ingenuity. In this work, we take a different approach: we investigate the discovery of data-driven RA functions, i.e, based directly on the performance of the resulting imitation policy. To this end, we leverage an LLM-guided evolutionary framework that efficiently explores the space of RA functions, yielding _Discovered Adversarial Imitation Learning_ (DAIL), the first meta-learnt AIL algorithm. Remarkably, DAIL generalises across unseen environments and policy optimization algorithms, outperforming the current state-of-the-art of _human-designed_ baselines. Finally, we analyse why DAIL leads to more stable training, offering novel insights into the role of RA functions in the stability of AIL.

Selecting high-quality candidates from large-scale datasets is critically important in resource-constrained applications such as drug discovery, precision medicine, and the alignment of large language models. While conformal selection methods offer a rigorous solution with False Discovery Rate (FDR) control, their applicability is confined to single-threshold scenarios (i.e., y > c) and overlooks practical needs for multi-condition selection, such as conjunctive or disjunctive conditions. In this work, we propose the Multi-Condition Conformal Selection (MCCS) algorithm, which extends conformal selection to scenarios with multiple conditions. In particular, we introduce a novel nonconformity score with regional monotonicity for conjunctive conditions and a global Benjamini–Hochberg (BH) procedure for disjunctive conditions, thereby establishing finite-sample FDR control with theoretical guarantees. The integration of these components enables the proposed method to achieve rigorous FDR-controlled selection in various multi-condition environments. Extensive experiments validate the superiority of MCCS over baselines, its generalizability across diverse condition combinations, different real-world modalities, and multi-task scalability.

In multi-task Bayesian optimization, the goal is to leverage experience from optimizing existing tasks to improve the efficiency of optimizing new ones. While approaches using multi-task Gaussian processes or deep kernel transfer exist, the performance improvement is marginal when scaling beyond a moderate number of tasks. We introduce **BOLT**, an initialization-only transfer strategy that distills prior BO runs into an LLM which proposes candidates for new tasks, while the surrogate at test time remains single-task. The LLM is periodically fine-tuned on top solutions from completed runs, creating a closed loop where better BO outputs yield better initializations over time. This decoupled design scales to roughly 1500 tasks without the saturation observed for shared-surrogate MTBO and adds only a small, amortized overhead relative to the BO inner loops. We evaluate on two domains: database query optimization and antimicrobial peptide design. We demonstrate that LLM-generated initializations steadily improve and accelerate BO, and with sufficient fine-tuning, a few LLM samples often match or surpass full ''from-scratch'' BO with far fewer oracle calls.

Drug target interaction (DTI) prediction is a cornerstone of computational drug discovery, enabling rational design, repurposing, and mechanistic insights. While deep learning has advanced DTI modeling, existing approaches primarily rely on SMILES–protein pairs and fail to exploit the rich multimodal information available for small molecules and proteins. Inspired by recent successes in multimodal molecular property prediction, we introduce GRAM-DTI, a pre-training framework that integrates multimodal small molecule and protein inputs into a unified representation. GRAM-DTI extends volume-based contrastive learning to four modalities, capturing higher-order semantic alignment beyond conventional pairwise approaches. To handle modality informativeness, we propose adaptive modality dropout, dynamically regulating each modality’s contribution during pretraining. Additionally, IC50 activity measurements, when available, are incorporated as weak supervision to ground representations in biologically meaningful interaction strengths. Experiments on four publicly available datasets demonstrate that GRAM-DTI consistently outperforms state-of-the-art baselines. Our results highlight the benefits of higher-order multimodal alignment, adaptive modality utilization, and auxiliary supervision for robust and generalizable DTI prediction.

Real world data often exhibits unknown, instance-specific symmetries that rarely exactly match a transformation group $G$ fixed a priori. Class-pose decompositions aim to create disentangled representations by factoring inputs into invariant features and a pose $g\in G$ defined relative to a training-dependent, \emph{arbitrary} canonical representation. We introduce \textsc{recon}, a class-pose agnostic \emph{canonical orientation normalization} that corrects arbitrary canonicals via a simple right-multiplication, yielding \emph{natural}, data-aligned canonicalizations. This enables (i) unsupervised discovery of instance-specific pose distributions, (ii) detection of out-of-distribution poses and (iii) a plug-and-play \emph{test-time canonicalization layer}. This layer can be attached on top of any pre-trained model to infuse group invariance, improving its performance without retraining. We demonstrate results on 2D image benchmarks and extend unsupervised instance-level pose discovery to 3D groups.

Fast, unconditional 3D generative models can now produce high-quality molecules, but adapting them for specific design tasks often requires costly retraining. To address this, we introduce Interpolate-Integrate and Replacement Guidance, two training-free, inference-time conditioning strategies that provide control over E(3)-equivariant flow-matching models. Our methods generate bioisosteric 3D molecules by conditioning on seed ligands or fragment sets to preserve key determinants like shape and pharmacophore patterns, without requiring the original fragment atoms to be present. We demonstrate their effectiveness on three drug-relevant tasks: natural product ligand hopping, bioisosteric fragment merging, and pharmacophore merging.

A well-known pitfall of molecular generative models is that they are not guaranteed to generate synthesizable molecules. Existing solutions for this problem often struggle to effectively navigate exponentially large combinatorial space of synthesizable molecules and suffer from poor coverage. To address this problem, we introduce ReaSyn, an iterative generative pathway refinement framework that obtains synthesizable analogs to input molecules by projecting them onto synthesizable space. Specifically, we propose a simple synthetic pathway representation that allows for generating pathways in both bottom-up and top-down traversal of synthetic trees. We design ReaSyn so that both bottom-up and top-down pathways can be sampled with a single unified autoregressive model. ReaSyn can thus iteratively refine subtrees of generated synthetic trees in a bidirectional manner. Further, we introduce a discrete flow model that refines the generated pathway at the entire pathway level with edit operations: insertion, deletion, and substitution. The iterative refinement cycle of (1) bottom-up decoding, (2) top-down decoding, and (3) holistic editing constitutes a powerful pathway reasoning strategy, allowing the model to explore the vast space of synthesizable molecules. Experimentally, ReaSyn achieves the highest reconstruction rate and pathway diversity in synthesizable molecule reconstruction and the highest optimization performance in synthesizable goal-directed molecular optimization, and significantly outperforms previous synthesizable projection methods in synthesizable hit expansion. These results highlight ReaSyn's superior ability to navigate combinatorially-large synthesizable chemical space.

Diffusion language models (DLMs) generate tokens in parallel through iterative denoising, which can reduce latency and enable bidirectional conditioning. However, the safety risks posed by jailbreak attacks that exploit this inference mechanism are not well understood. In this paper, we reveal that DLMs have a critical vulnerability stemming from their iterative denoising process and propose a countermeasure. Specifically, our investigation identifies that if an affirmative token for a harmful query appears at an intermediate step, subsequent denoising can be steered toward a harmful response even in aligned models. Furthermore, we demonstrate that the vulnerability enables existing optimization-based jailbreak attacks to be applied to MDLMs. Building on this analysis, we propose a novel safety alignment method tailored to DLMs that trains models to generate safe responses from contaminated intermediate denoising steps containing affirmative tokens. Our experiments indicate that the proposed method significantly mitigates the vulnerability with minimal impact on task performance. Furthermore, our method also improves robustness against conventional jailbreak attacks. Our work underscores the need for DLM-specific safety research. Our code is available at [https://github.com/mdl-lab/dlm-priming-vulnerability](https://github.com/mdl-lab/dlm-priming-vulnerability).

The efficiency of Logic Optimization (LO) has become one of the key bottlenecks in chip design. To prompt efficient LO, many graph-based machine learning (ML) methods, such as graph neural networks (GNNs), have been proposed to predict and prune a large number of ineffective subgraphs of the LO heuristics. However, the high inference cost and limited interpretability of these approaches severely limit their wide application to modern LO tools. To address this challenge, we propose a novel **H**ierarchical C**i**rcuit **S**ymbolic Discovery Framework, namely HIS, to learn a *lightweight* and *interpretable* symbolic function that can *accurately* identify ineffective subgraphs for efficient LO. Specifically, HIS proposes a hierarchical tree structure to represent the circuit symbolic function, where every layer of the symbolic tree performs an efficient and interpretable message passing to capture the structural information of the circuit graph. To learn the hierarchical tree, we propose a circuit symbolic generation framework that leverages reinforcement learning to optimize a structure-aware Transformer model for symbolic token generation. To the best of our knowledge, HIS is *the first* approach to discover an efficient, interpretable, and high-performance symbolic function from the circuit graph for efficient LO. Experiments on two widely used circuit benchmarks show that the learned graph symbolic functions outperform previous state-of-the-art approaches in terms of efficiency and optimization performance. Moreover, we integrate HIS with the Mfs2 heuristic, one of the most time-consuming LO heuristics. Results show that HIS significantly enhances both its efficiency and optimization performance on a CPU-based machine, achieving an average runtime improvement of 27.22% and a 6.95% reduction in circuit size.

On-the-Fly Category Discovery (OCD) aims to address the limitations of transductive learning and closed-set prediction in category discovery tasks by enabling real-time classification of potential future categories using prior knowledge. Existing OCD approaches typically rely on hash-based encodings that map features into low-dimensional hash spaces and directly classify test samples using these encodings. Despite efforts to mitigate the sensitivity of hash functions during testing, these methods still suffer from severe overestimation of the number of categories. In this work, we thoroughly analyze the practical limitations of current OCD methods and formally identify a performance lower bound for the task. Based on this insight, we reformulate OCD into two sub-tasks: Open-Set Recognition and an Fully Novel OCD setting. For all samples, we employ a soft class thresholding strategy to directly detect known classes, which significantly enhances the deployment feasibility of OCD to downstream tasks. For outlier samples, we propose Adaptive Gaussian Expansion (AGE), a dynamic category discovery method that models the Probability Density Functions (PDF) of different classes to uncover potential novel categories in real time. Extensive experiments across multiple datasets demonstrate that our method achieves state-of-the-art performance.