Zexuan Zhu

Qianwei Yang, Dong Xu, Zhangfan Yang et al.

Drug discovery can be viewed as a combinatorial search over an immense chemical space, motivating the development of deep generative models for de novo molecular design. Among these, GPT-based molecular language models (MLM) have shown strong molecular design performance by learning chemical syntax and semantics from large-scale data. However, existing MLMs face two fundamental limitations: they inadequately capture the graph-structured nature of molecules when formulated as next-token prediction problems, and they typically lack explicit mechanisms for target-aware generation. Here, we propose SoftMol, a unified framework that co-designs molecular representation, model architecture, and search strategy for target-aware molecular generation. SoftMol introduces soft fragments, a rule-free block representation of SMILES that enables diffusion-native modeling, and develops SoftBD, the first block-diffusion molecular language model that combines local bidirectional diffusion with autoregressive generation under molecular structural constraints. To favor generated molecules with high drug-likeness and synthetic accessibility, SoftBD is trained on a carefully curated dataset named ZINC-Curated. SoftMol further integrates a gated Monte Carlo tree search to assemble fragments in a target-aware manner. Experimental results show that, compared with current state-of-the-art models, SoftMol achieves 100% chemical validity, improves binding affinity by 9.7%, yields a 2-3x increase in molecular diversity, and delivers a 6.6x speedup in inference efficiency. Code is available at https://github.com/szu-aicourse/softmol

Dong Xu, Jiantao Wu, Qihua Pan et al.

Drug-drug interaction (DDI) prediction is central to drug discovery and clinical development, particularly in the context of increasingly prevalent polypharmacy. Although existing computational methods achieve strong performance on standard benchmarks, they often fail to generalize to realistic deployment scenarios, where most candidate drug pairs involve previously unseen drugs and validated interactions are scarce. We demonstrate that proximity in the embedding spaces of prevailing molecule-centric DDI models does not reliably correspond to interaction labels, and that simply scaling up model capacity therefore fails to improve generalization. To address these limitations, we propose GenRel-DDI, a generalizable relation learning framework that reformulates DDI prediction as a relation-centric learning problem, in which interaction representations are learned independently of drug identities. This relation-level abstraction enables the capture of transferable interaction patterns that generalize to unseen drugs and novel drug pairs. Extensive experiments across multiple benchmark demonstrate that GenRel-DDI consistently and significantly outperforms state-of-the-art methods, with particularly large gains on strict entity-disjoint evaluations, highlighting the effectiveness and practical utility of relation learning for robust DDI prediction. The code is available at https://github.com/SZU-ADDG/GenRel-DDI.

Dong Xu, Qihua Pan, Sisi Yuan et al.

Molecular generative models, often employing GPT-style language modeling on molecular string representations, have shown promising capabilities when scaled to large datasets and model sizes. However, it remains unclear and subject to debate whether these models adhere to predictable scaling laws under fixed computational budgets, which is a crucial understanding for optimally allocating resources between model size, data volume, and molecular representation. In this study, we systematically investigate the scaling behavior of molecular language models across both pretraining and downstream tasks. We train 300 models and conduct over 10,000 experiments, rigorously controlling compute budgets while independently varying model size, number of training tokens, and molecular representation. Our results demonstrate clear scaling laws in molecular models for both pretraining and downstream transfer, reveal the substantial impact of molecular representation on performance, and explain previously observed inconsistencies in scaling behavior for molecular generation. Additionally, we publicly release the largest library of molecular language models to date to facilitate future research and development. Code and models are available at https://github.com/SZU-ADDG/MLM-Scaling.

Wei Zhou, Wuyang Li, Junkai Ji et al.

Multi-objective re-ranking has become a critical component of modern multi-stage recommender systems, as it tasked to balance multiple conflicting objectives such as accuracy, diversity, and fairness. Existing multi-objective re-ranking methods typically optimize aggregate objectives at the item level using static or handcrafted preference weights. This design overlooks that users inherently exhibit Pareto-optimal preferences at the intent level, reflecting personalized trade-offs among objectives rather than fixed weight combinations. Moreover, most approaches treat re-ranking task for each user as an isolated problem, and repeatedly learn the preferences from scratch. Such a paradigm not only incurs high computational cost, but also ignores the fact that users often share similar preference trade-off structures across objectives. Inspired by the existence of homogeneous multi-objective optimization spaces where Pareto-optimal patterns are transferable, we propose PreferRec, a novel framework that explicitly models and transfers Pareto preferences across users. Specifically, PreferRec is built upon three tightly coupled components: Preference-Aware Pareto Learning aims to capture user intrinsic trade-offs among multiple conflicting objectives at the intent level. By learning Pareto preference representations from re-ranking populations, this component explicitly models how users prioritize different objectives under diverse contexts. Knowledge-Guided Transfer facilitates efficient cross-user knowledge transfer by distilling shared optimization patterns across homogeneous optimization spaces. The transferred knowledge is then used to guide solution selection and personalized re-ranking, biasing the optimization process toward high-quality regions of the Pareto front while preserving user-specific preference characteristics.

Wenjing Hong, Zhonghua Rong, Li Wang et al.

Large Language Models (LLMs) have been widely deployed, especially through free Web-based applications that expose them to diverse user-generated inputs, including those from long-tail distributions such as low-resource languages and encrypted private data. This open-ended exposure increases the risk of jailbreak attacks that undermine model safety alignment. While recent studies have shown that leveraging long-tail distributions can facilitate such jailbreaks, existing approaches largely rely on handcrafted rules, limiting the systematic evaluation of these security and privacy vulnerabilities. In this work, we present EvoJail, an automated framework for discovering long-tail distribution attacks via multi-objective evolutionary search. EvoJail formulates long-tail attack prompt generation as a multi-objective optimization problem that jointly maximizes attack effectiveness and minimizes output perplexity, and introduces a semantic-algorithmic solution representation to capture both high-level semantic intent and low-level structural transformations of encryption-decryption logic. Building upon this representation, EvoJail integrates LLM-assisted operators into a multi-objective evolutionary framework, enabling adaptive and semantically informed mutation and crossover for efficiently exploring a highly structured and open-ended search space. Extensive experiments demonstrate that EvoJail consistently discovers diverse and effective long-tail jailbreak strategies, achieving competitive performance with existing methods in both individual and ensemble level.

Qihua Pan, Dong Xu, Jenna Xinyi Yao et al.

Powerful AI tools for drug discovery reside in isolated web apps, desktop programs, and code libraries. Such fragmentation forces scientists to manage incompatible interfaces and specialized scripts, which can be a cumbersome and repetitive process. To address this issue, a Full-pROcess druG dEsign ageNT, named FROGENT, has been proposed. Specifically, FROGENT utilizes a Large Language Model and the Model Context Protocol to integrate multiple dynamic biochemical databases, extensible tool libraries, and task-specific AI models. This agentic framework allows FROGENT to execute complicated drug discovery workflows dynamically, including component tasks such as target identification, molecule generation and retrosynthetic planning. FROGENT has been evaluated on eight benchmarks that cover various aspects of drug discovery, such as knowledge retrieval, property prediction, virtual screening, mechanistic analysis, molecular design, and synthesis. It was compared against six increasingly advanced ReAct-style agents that support code execution and literature searches. Empirical results demonstrated that FROGENT triples the best baseline performance in hit-finding and doubles it in interaction profiling, significantly outperforming both the open-source model Qwen3-32B and the commercial model GPT-4o. In addition, real-world cases have been utilized to validate the practicability and generalization of FROGENT. This development suggests that streamlining the agentic drug discovery pipeline can significantly enhance researcher productivity.

Junkai Ji, Zhangfan Yang, Dong Xu et al.

Drug discovery is a time-consuming and expensive process, with traditional high-throughput and docking-based virtual screening hampered by low success rates and limited scalability. Recent advances in generative modelling, including autoregressive, diffusion, and flow-based approaches, have enabled de novo ligand design beyond the limits of enumerative screening. Yet these models often suffer from inadequate generalization, limited interpretability, and an overemphasis on binding affinity at the expense of key pharmacological properties, thereby restricting their translational utility. Here we present Trio, a molecular generation framework integrating fragment-based molecular language modeling, reinforcement learning, and Monte Carlo tree search, for effective and interpretable closed-loop targeted molecular design. Through the three key components, Trio enables context-aware fragment assembly, enforces physicochemical and synthetic feasibility, and guides a balanced search between the exploration of novel chemotypes and the exploitation of promising intermediates within protein binding pockets. Experimental results show that Trio reliably achieves chemically valid and pharmacologically enhanced ligands, outperforming state-of-the-art approaches with improved binding affinity (+7.85%), drug-likeness (+11.10%) and synthetic accessibility (+12.05%), while expanding molecular diversity more than fourfold.

Sisi Yuan, Jiehuang Chen, Junchuang Cai et al.

Protein inverse folding, the task of predicting amino acid sequences for desired structures, is pivotal for de novo protein design. However, existing GNN-based methods typically suffer from restricted receptive fields that miss long-range dependencies and a "single-pass" inference paradigm that leads to error accumulation. To address these bottlenecks, we propose RIGA-Fold, a framework that synergizes Recurrent Interaction with Geometric Awareness. At the micro-level, we introduce a Geometric Attention Update (GAU) module where edge features explicitly serve as attention keys, ensuring strictly SE(3)-invariant local encoding. At the macro-level, we design an attention-based Global Context Bridge that acts as a soft gating mechanism to dynamically inject global topological information. Furthermore, to bridge the gap between structural and sequence modalities, we introduce an enhanced variant, RIGA-Fold*, which integrates trainable geometric features with frozen evolutionary priors from ESM-2 and ESM-IF via a dual-stream architecture. Finally, a biologically inspired ``predict-recycle-refine'' strategy is implemented to iteratively denoise sequence distributions. Extensive experiments on CATH 4.2, TS50, and TS500 benchmarks demonstrate that our geometric framework is highly competitive, while RIGA-Fold* significantly outperforms state-of-the-art baselines in both sequence recovery and structural consistency.

Hang Guo, Tao Dai, Yuanchao Bai et al.

Designing single-task image restoration models for specific degradation has seen great success in recent years. To achieve generalized image restoration, all-in-one methods have recently been proposed and shown potential for multiple restoration tasks using one single model. Despite the promising results, the existing all-in-one paradigm still suffers from high computational costs as well as limited generalization on unseen degradations. In this work, we introduce an alternative solution to improve the generalization of image restoration models. Drawing inspiration from recent advancements in Parameter Efficient Transfer Learning (PETL), we aim to tune only a small number of parameters to adapt pre-trained restoration models to various tasks. However, current PETL methods fail to generalize across varied restoration tasks due to their homogeneous representation nature. To this end, we propose AdaptIR, a Mixture-of-Experts (MoE) with orthogonal multi-branch design to capture local spatial, global spatial, and channel representation bases, followed by adaptive base combination to obtain heterogeneous representation for different degradations. Extensive experiments demonstrate that our AdaptIR achieves stable performance on single-degradation tasks, and excels in hybrid-degradation tasks, with fine-tuning only 0.6% parameters for 8 hours.

Wei Zhou, Yue Shen, Junkai Ji et al.

User interests typically encompass both long-term preferences and short-term intentions, reflecting the dynamic nature of user behaviors across different timeframes. The uneven temporal distribution of user interactions highlights the evolving patterns of interests, making it challenging to accurately capture shifts in interests using comprehensive historical behaviors. To address this, we propose SLSRec, a novel Session-based model with the fusion of Long- and Short-term Recommendations that effectively captures the temporal dynamics of user interests by segmenting historical behaviors over time. Unlike conventional models that combine long- and short-term user interests into a single representation, compromising recommendation accuracy, SLSRec utilizes a self-supervised learning framework to disentangle these two types of interests. A contrastive learning strategy is introduced to ensure accurate calibration of long- and short-term interest representations. Additionally, an attention-based fusion network is designed to adaptively aggregate interest representations, optimizing their integration to enhance recommendation performance. Extensive experiments on three public benchmark datasets demonstrate that SLSRec consistently outperforms state-of-the-art models while exhibiting superior robustness across various scenarios.We will release all source code upon acceptance.

Dong Xu, Zhangfan Yang, Ka-chun Wong et al.

Breakthroughs in high-accuracy protein structure prediction, such as AlphaFold, have established receptor-based molecule design as a critical driver for rapid early-phase drug discovery. However, most approaches still struggle to balance pocket-specific geometric fit with strict valence and synthetic constraints. To resolve this trade-off, a Retrieval-Enhanced Aligned Diffusion termed READ is introduced, which is the first to merge molecular Retrieval-Augmented Generation with an SE(3)-equivariant diffusion model. Specifically, a contrastively pre-trained encoder aligns atom-level representations during training, then retrieves graph embeddings of pocket-matched scaffolds to guide each reverse-diffusion step at inference. This single mechanism can inject real-world chemical priors exactly where needed, producing valid, diverse, and shape-complementary ligands. Experimental results demonstrate that READ can achieve very competitive performance in CBGBench, surpassing state-of-the-art generative models and even native ligands. That suggests retrieval and diffusion can be co-optimized for faster, more reliable structure-based drug design.

Zhangfan Yang, Junkai Ji, Shan He et al.

Molecular docking is a crucial step in drug development, which enables the virtual screening of compound libraries to identify potential ligands that target proteins of interest. However, the computational complexity of traditional docking models increases as the size of the compound library increases. Recently, deep learning algorithms can provide data-driven research and development models to increase the speed of the docking process. Unfortunately, few models can achieve superior screening performance compared to that of traditional models. Therefore, a novel deep learning-based docking approach named Dockformer is introduced in this study. Dockformer leverages multimodal information to capture the geometric topology and structural knowledge of molecules and can directly generate binding conformations with the corresponding confidence measures in an end-to-end manner. The experimental results show that Dockformer achieves success rates of 90.53% and 82.71% on the PDBbind core set and PoseBusters benchmarks, respectively, and more than a 100-fold increase in the inference process speed, outperforming almost all state-of-the-art docking methods. In addition, the ability of Dockformer to identify the main protease inhibitors of coronaviruses is demonstrated in a real-world virtual screening scenario. Considering its high docking accuracy and screening efficiency, Dockformer can be regarded as a powerful and robust tool in the field of drug design.

Dong Xu, Zhangfan Yang, Jenna Xinyi Yao et al.

Three-dimensional generative models increasingly drive structure-based drug discovery, yet it remains constrained by the scarce publicly available protein-ligand complexes. Under such data scarcity, almost all existing pipelines struggle to learn transferable geometric priors and consequently overfit to training-set biases. As such, we present IBEX, an Information-Bottleneck-EXplored coarse-to-fine pipeline to tackle the chronic shortage of protein-ligand complex data in structure-based drug design. Specifically, we use PAC-Bayesian information-bottleneck theory to quantify the information density of each sample. This analysis reveals how different masking strategies affect generalization and indicates that, compared with conventional de novo generation, the constrained Scaffold Hopping task endows the model with greater effective capacity and improved transfer performance. IBEX retains the original TargetDiff architecture and hyperparameters for training to generate molecules compatible with the binding pocket; it then applies an L-BFGS optimization step to finely refine each conformation by optimizing five physics-based terms and adjusting six translational and rotational degrees of freedom in under one second. With only these modifications, IBEX raises the zero-shot docking success rate on CBGBench CrossDocked2020-based from 53% to 64%, improves the mean Vina score from $-7.41 kcal mol^{-1}$ to $-8.07 kcal mol^{-1}$, and achieves the best median Vina energy in 57 of 100 pockets versus 3 for the original TargetDiff. IBEX also increases the QED by 25%, achieves state-of-the-art validity and diversity, and markedly reduces extrapolation error.

Zhengping Liang, Jian Zhang, Liang Feng et al.

The placement scheme of virtual machines (VMs) to physical servers (PSs) is crucial to lowering operational cost for cloud providers. Evolutionary algorithms (EAs) have been performed promising-solving on virtual machine placement (VMP) problems in the past. However, as growing demand for cloud services, the existing EAs fail to implement in large-scale virtual machine placement (LVMP) problem due to the high time complexity and poor scalability. Recently, the multi-factorial optimization (MFO) technology has surfaced as a new search paradigm in evolutionary computing. It offers the ability to evolve multiple optimization tasks simultaneously during the evolutionary process. This paper aims to apply the MFO technology to the LVMP problem in heterogeneous environment. Firstly, we formulate a deployment cost based VMP problem in the form of the MFO problem. Then, a multi-factorial evolutionary algorithm (MFEA) embedded with greedy-based allocation operator is developed to address the established MFO problem. After that, a re-migration and merge operator is designed to offer the integrated solution of the LVMP problem from the solutions of MFO problem. To assess the effectiveness of our proposed method, the simulation experiments are carried on large-scale and extra large-scale VMs test data sets. The results show that compared with various heuristic methods, our method could shorten optimization time significantly and offer a competitive placement solution for the LVMP problem in heterogeneous environment.

Zhengping Liang, Weiqi Liang, Xiuju Xu et al.

Multi-tasking optimization can usually achieve better performance than traditional single-tasking optimization through knowledge transfer between tasks. However, current multi-tasking optimization algorithms have some deficiencies. For high similarity problems, the knowledge that can accelerate the convergence rate of tasks has not been fully taken advantages of. For low similarity problems, the probability of generating negative transfer is high, which may result in optimization performance degradation. In addition, some knowledge transfer methods proposed previously do not fully consider how to deal with the situation in which the population falls into local optimum. To solve these issues, a two-stage adaptive knowledge transfer evolutionary multi-tasking optimization algorithm based on population distribution, labeled as EMT-PD, is proposed. EMT-PD can accelerate and improve the convergence performance of tasks based on the knowledge extracted from the probability model that reflects the search trend of the whole population. At the first transfer stage, an adaptive weight is used to adjust the step size of individual's search, which can reduce the impact of negative transfer. At the second stage of knowledge transfer, the individual's search range is further adjusted dynamically, which can improve the diversity of population and be beneficial for jumping out of local optimum. Experimental results on multi-tasking multi-objective optimization test suites show that EMT-PD is superior to other six state-of-the-art evolutionary multi/single-tasking algorithms. To further investigate the effectiveness of EMT-PD on many-objective optimization problems, a multi-tasking many-objective test suite is also designed in this paper. The experimental results on the new test suite also demonstrate the competitiveness of EMT-PD.

Bingshui Da, Yew-Soon Ong, Liang Feng et al.

In this report, we suggest nine test problems for multi-task single-objective optimization (MTSOO), each of which consists of two single-objective optimization tasks that need to be solved simultaneously. The relationship between tasks varies between different test problems, which would be helpful to have a comprehensive evaluation of the MFO algorithms. It is expected that the proposed test problems will germinate progress the field of the MTSOO research.

Yu Sun, Ke Tang, Zexuan Zhu et al.

Incremental learning with concept drift has often been tackled by ensemble methods, where models built in the past can be re-trained to attain new models for the current data. Two design questions need to be addressed in developing ensemble methods for incremental learning with concept drift, i.e., which historical (i.e., previously trained) models should be preserved and how to utilize them. A novel ensemble learning method, namely Diversity and Transfer based Ensemble Learning (DTEL), is proposed in this paper. Given newly arrived data, DTEL uses each preserved historical model as an initial model and further trains it with the new data via transfer learning. Furthermore, DTEL preserves a diverse set of historical models, rather than a set of historical models that are merely accurate in terms of classification accuracy. Empirical studies on 15 synthetic data streams and 4 real-world data streams (all with concept drifts) demonstrate that DTEL can handle concept drift more effectively than 4 other state-of-the-art methods.