Unveiling Scaling Behaviors in Molecular Language Models: Effects of Model Size, Data, and Representation

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.

From Tokens to Blocks: A Block-Diffusion Perspective on Molecular Generation

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

Rethinking Drug-Drug Interaction Modeling as Generalizable Relation Learning

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.

An Efficient Evolutionary Algorithm for Few-for-Many Optimization

Few-for-many (F4M) optimization, recently introduced as a novel paradigm in multi-objective optimization, aims to find a small set of solutions that effectively handle a large number of conflicting objectives. Unlike traditional many-objective optimization methods, which typically attempt comprehensive coverage of the Pareto front, F4M optimization emphasizes finding a small representative solution set to efficiently address high-dimensional objective spaces. Motivated by the computational complexity and practical relevance of F4M optimization, this paper proposes a new evolutionary algorithm explicitly tailored for efficiently solving F4M optimization problems. Inspired by SMS-EMOA, our proposed approach employs a $(μ+1)$-evolution strategy guided by the objective of F4M optimization. Furthermore, to facilitate rigorous performance assessment, we propose a novel benchmark test suite specifically designed for F4M optimization by leveraging the similarity between the R2 indicator and F4M formulations. Our test suite is highly flexible, allowing any existing multi-objective optimization problem to be transformed into a corresponding F4M instance via scalarization using the weighted Tchebycheff function. Comprehensive experimental evaluations on benchmarks demonstrate the superior performance of our algorithm compared to existing state-of-the-art algorithms, especially on instances involving a large number of objectives. The source code of the proposed algorithm will be released publicly. Source code is available at https://github.com/MOL-SZU/SoM-EMOA.

Toward Closed-loop Molecular Discovery via Language Model, Property Alignment and Strategic Search

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. By combining generalization, plausibility, and interpretability, Trio establishes a closed-loop generative paradigm that redefines how chemical space can be navigated, offering a transformative foundation for the next era of AI-driven drug discovery.

Reimagining Target-Aware Molecular Generation through Retrieval-Enhanced Aligned Diffusion

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.

Dockformer: A transformer-based molecular docking paradigm for large-scale virtual screening

Molecular docking enables virtual screening of compound libraries to identify potential ligands that target proteins of interest, a crucial step in drug development; however, as the size of the compound library increases, the computational complexity of traditional docking models increases. 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.

AdaptIR: Parameter Efficient Multi-task Adaptation for Pre-trained Image Restoration Models

Pre-training has shown promising results on various image restoration tasks, which is usually followed by full fine-tuning for each specific downstream task (e.g., image denoising). However, such full fine-tuning usually suffers from the problems of heavy computational cost in practice, due to the massive parameters of pre-trained restoration models, thus limiting its real-world applications. Recently, Parameter Efficient Transfer Learning (PETL) offers an efficient alternative solution to full fine-tuning, yet still faces great challenges for pre-trained image restoration models, due to the diversity of different degradations. To address these issues, we propose AdaptIR, a novel parameter efficient transfer learning method for adapting pre-trained restoration models. Specifically, the proposed method consists of a multi-branch inception structure to orthogonally capture local spatial, global spatial, and channel interactions. In this way, it allows powerful representations under a very low parameter budget. Extensive experiments demonstrate that the proposed method can achieve comparable or even better performance than full fine-tuning, while only using 0.6% parameters. Code is available at https://github.com/csguoh/AdaptIR.

Multi-factorial Optimization for Large-scale Virtual Machine Placement in Cloud Computing

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.

A Two stage Adaptive Knowledge Transfer Evolutionary Multi-tasking Based on Population Distribution for Multi/Many-Objective Optimization

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 utilized fully. 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 increase the diversity of population and beneficial for jumping out of local optimum. Experimental results on multi-tasking multi-objective optimization test suites show that EMT-PD is superior to six state-of-the-art optimization algorithms. In order to further investigate the effectiveness of EMT-PD on many-objective optimization problems, a multi-tasking many-objective test suite is designed. The experimental results on it also demonstrate that EMT-PD has obvious competitiveness.