AdaptMol: Adaptive Fusion from Sequence String to Topological Structure for Few-shot Drug Discovery

Accurate molecular property prediction (MPP) is a critical step in modern drug development. However, the scarcity of experimental validation data poses a significant challenge to AI-driven research paradigms. Under few-shot learning scenarios, the quality of molecular representations directly dictates the theoretical upper limit of model performance. We present AdaptMol, a prototypical network integrating Adaptive multimodal fusion for Molecular representation. This framework employs a dual-level attention mechanism to dynamically integrate global and local molecular features derived from two modalities: SMILES sequences and molecular graphs. (1) At the local level, structural features such as atomic interactions and substructures are extracted from molecular graphs, emphasizing fine-grained topological information; (2) At the global level, the SMILES sequence provides a holistic representation of the molecule. To validate the necessity of multimodal adaptive fusion, we propose an interpretable approach based on identifying molecular active substructures to demonstrate that multimodal adaptive fusion can efficiently represent molecules. Extensive experiments on three commonly used benchmarks under 5-shot and 10-shot settings demonstrate that AdaptMol achieves state-of-the-art performance in most cases. The rationale-extracted method guides the fusion of two modalities and highlights the importance of both modalities.

EDBench: Large-Scale Electron Density Data for Molecular Modeling

Existing molecular machine learning force fields (MLFFs) generally focus on the learning of atoms, molecules, and simple quantum chemical properties (such as energy and force), but ignore the importance of electron density (ED) $\rho(r)$ in accurately understanding molecular force fields (MFFs). ED describes the probability of finding electrons at specific locations around atoms or molecules, which uniquely determines all ground state properties (such as energy, molecular structure, etc.) of interactive multi-particle systems according to the Hohenberg-Kohn theorem. However, the calculation of ED relies on the time-consuming first-principles density functional theory (DFT) which leads to the lack of large-scale ED data and limits its application in MLFFs. In this paper, we introduce EDBench, a large-scale, high-quality dataset of ED designed to advance learning-based research at the electronic scale. Built upon the PCQM4Mv2, EDBench provides accurate ED data, covering 3.3 million molecules. To comprehensively evaluate the ability of models to understand and utilize electronic information, we design a suite of ED-centric benchmark tasks spanning prediction, retrieval, and generation. Our evaluation on several state-of-the-art methods demonstrates that learning from EDBench is not only feasible but also achieves high accuracy. Moreover, we show that learning-based method can efficiently calculate ED with comparable precision while significantly reducing the computational cost relative to traditional DFT calculations. All data and benchmarks from EDBench will be freely available, laying a robust foundation for ED-driven drug discovery and materials science.

Enhancing Chemical Reaction and Retrosynthesis Prediction with Large Language Model and Dual-task Learning

Chemical reaction and retrosynthesis prediction are fundamental tasks in drug discovery. Recently, large language models (LLMs) have shown potential in many domains. However, directly applying LLMs to these tasks faces two major challenges: (i) lacking a large-scale chemical synthesis-related instruction dataset; (ii) ignoring the close correlation between reaction and retrosynthesis prediction for the existing fine-tuning strategies. To address these challenges, we propose ChemDual, a novel LLM framework for accurate chemical synthesis. Specifically, considering the high cost of data acquisition for reaction and retrosynthesis, ChemDual regards the reaction-and-retrosynthesis of molecules as a related recombination-and-fragmentation process and constructs a large-scale of 4.4 million instruction dataset. Furthermore, ChemDual introduces an enhanced LLaMA, equipped with a multi-scale tokenizer and dual-task learning strategy, to jointly optimize the process of recombination and fragmentation as well as the tasks between reaction and retrosynthesis prediction. Extensive experiments on Mol-Instruction and USPTO-50K datasets demonstrate that ChemDual achieves state-of-the-art performance in both predictions of reaction and retrosynthesis, outperforming the existing conventional single-task approaches and the general open-source LLMs. Through molecular docking analysis, ChemDual generates compounds with diverse and strong protein binding affinity, further highlighting its strong potential in drug design.

An All-Atom Generative Model for Designing Protein Complexes

Proteins typically exist in complexes, interacting with other proteins or biomolecules to perform their specific biological roles. Research on single-chain protein modeling has been extensively and deeply explored, with advancements seen in models like the series of ESM and AlphaFold. Despite these developments, the study and modeling of multi-chain proteins remain largely uncharted, though they are vital for understanding biological functions. Recognizing the importance of these interactions, we introduce APM (All-Atom Protein Generative Model), a model specifically designed for modeling multi-chain proteins. By integrating atom-level information and leveraging data on multi-chain proteins, APM is capable of precisely modeling inter-chain interactions and designing protein complexes with binding capabilities from scratch. It also performs folding and inverse-folding tasks for multi-chain proteins. Moreover, APM demonstrates versatility in downstream applications: it achieves enhanced performance through supervised fine-tuning (SFT) while also supporting zero-shot sampling in certain tasks, achieving state-of-the-art results. Code will be released at https://github.com/bytedance/apm.

Property Enhanced Instruction Tuning for Multi-task Molecule Generation with Large Language Models

Large language models (LLMs) are widely applied in various natural language processing tasks such as question answering and machine translation. However, due to the lack of labeled data and the difficulty of manual annotation for biochemical properties, the performance for molecule generation tasks is still limited, especially for tasks involving multi-properties constraints. In this work, we present a two-step framework PEIT (Property Enhanced Instruction Tuning) to improve LLMs for molecular-related tasks. In the first step, we use textual descriptions, SMILES, and biochemical properties as multimodal inputs to pre-train a model called PEIT-GEN, by aligning multi-modal representations to synthesize instruction data. In the second step, we fine-tune existing open-source LLMs with the synthesized data, the resulting PEIT-LLM can handle molecule captioning, text-based molecule generation, molecular property prediction, and our newly proposed multi-constraint molecule generation tasks. Experimental results show that our pre-trained PEIT-GEN outperforms MolT5 and BioT5 in molecule captioning, demonstrating modalities align well between textual descriptions, structures, and biochemical properties. Furthermore, PEIT-LLM shows promising improvements in multi-task molecule generation, proving the scalability of the PEIT framework for various molecular tasks. We release the code, constructed instruction data, and model checkpoints in https://github.com/chenlong164/PEIT.

S$^2$DN: Learning to Denoise Unconvincing Knowledge for Inductive Knowledge Graph Completion

Inductive Knowledge Graph Completion (KGC) aims to infer missing facts between newly emerged entities within knowledge graphs (KGs), posing a significant challenge. While recent studies have shown promising results in inferring such entities through knowledge subgraph reasoning, they suffer from (i) the semantic inconsistencies of similar relations, and (ii) noisy interactions inherent in KGs due to the presence of unconvincing knowledge for emerging entities. To address these challenges, we propose a Semantic Structure-aware Denoising Network (S$^2$DN) for inductive KGC. Our goal is to learn adaptable general semantics and reliable structures to distill consistent semantic knowledge while preserving reliable interactions within KGs. Specifically, we introduce a semantic smoothing module over the enclosing subgraphs to retain the universal semantic knowledge of relations. We incorporate a structure refining module to filter out unreliable interactions and offer additional knowledge, retaining robust structure surrounding target links. Extensive experiments conducted on three benchmark KGs demonstrate that S$^2$DN surpasses the performance of state-of-the-art models. These results demonstrate the effectiveness of S$^2$DN in preserving semantic consistency and enhancing the robustness of filtering out unreliable interactions in contaminated KGs.

Balancing property optimization and constraint satisfaction for constrained multi-property molecular optimization

Molecular optimization, which aims to discover improved molecules from a vast chemical search space, is a critical step in chemical development. Various artificial intelligence technologies have demonstrated high effectiveness and efficiency on molecular optimization tasks. However, few of these technologies focus on balancing property optimization with constraint satisfaction, making it difficult to obtain high-quality molecules that not only possess desirable properties but also meet various constraints. To address this issue, we propose a constrained multi-property molecular optimization framework (CMOMO), which is a flexible and efficient method to simultaneously optimize multiple molecular properties while satisfying several drug-like constraints. CMOMO improves multiple properties of molecules with constraints based on dynamic cooperative optimization, which dynamically handles the constraints across various scenarios. Besides, CMOMO evaluates multiple properties within discrete chemical spaces cooperatively with the evolution of molecules within an implicit molecular space to guide the evolutionary search. Experimental results show the superior performance of the proposed CMOMO over five state-of-the-art molecular optimization methods on two benchmark tasks of simultaneously optimizing multiple non-biological activity properties while satisfying two structural constraints. Furthermore, the practical applicability of CMOMO is verified on two practical tasks, where it identified a collection of candidate ligands of $\beta$2-adrenoceptor GPCR and candidate inhibitors of glycogen synthase kinase-3$\beta$ with high properties and under drug-like constraints.

Y-Mol: A Multiscale Biomedical Knowledge-Guided Large Language Model for Drug Development

Large Language Models (LLMs) have recently demonstrated remarkable performance in general tasks across various fields. However, their effectiveness within specific domains such as drug development remains challenges. To solve these challenges, we introduce \textbf{Y-Mol}, forming a well-established LLM paradigm for the flow of drug development. Y-Mol is a multiscale biomedical knowledge-guided LLM designed to accomplish tasks across lead compound discovery, pre-clinic, and clinic prediction. By integrating millions of multiscale biomedical knowledge and using LLaMA2 as the base LLM, Y-Mol augments the reasoning capability in the biomedical domain by learning from a corpus of publications, knowledge graphs, and expert-designed synthetic data. The capability is further enriched with three types of drug-oriented instructions: description-based prompts from processed publications, semantic-based prompts for extracting associations from knowledge graphs, and template-based prompts for understanding expert knowledge from biomedical tools. Besides, Y-Mol offers a set of LLM paradigms that can autonomously execute the downstream tasks across the entire process of drug development, including virtual screening, drug design, pharmacological properties prediction, and drug-related interaction prediction. Our extensive evaluations of various biomedical sources demonstrate that Y-Mol significantly outperforms general-purpose LLMs in discovering lead compounds, predicting molecular properties, and identifying drug interaction events.

MoFormer: Multi-objective Antimicrobial Peptide Generation Based on Conditional Transformer Joint Multi-modal Fusion Descriptor

Deep learning holds a big promise for optimizing existing peptides with more desirable properties, a critical step towards accelerating new drug discovery. Despite the recent emergence of several optimized Antimicrobial peptides(AMP) generation methods, multi-objective optimizations remain still quite challenging for the idealism-realism tradeoff. Here, we establish a multi-objective AMP synthesis pipeline (MoFormer) for the simultaneous optimization of multi-attributes of AMPs. MoFormer improves the desired attributes of AMP sequences in a highly structured latent space, guided by conditional constraints and fine-grained multi-descriptor.We show that MoFormer outperforms existing methods in the generation task of enhanced antimicrobial activity and minimal hemolysis. We also utilize a Pareto-based non-dominated sorting algorithm and proxies based on large model fine-tuning to hierarchically rank the candidates. We demonstrate substantial property improvement using MoFormer from two perspectives: (1) employing molecular simulations and scoring interactions among amino acids to decipher the structure and functionality of AMPs; (2) visualizing latent space to examine the qualities and distribution features, verifying an effective means to facilitate multi-objective optimization AMPs with design constraints

HMAMP: Hypervolume-Driven Multi-Objective Antimicrobial Peptides Design

Antimicrobial peptides (AMPs) have exhibited unprecedented potential as biomaterials in combating multidrug-resistant bacteria. Despite the increasing adoption of artificial intelligence for novel AMP design, challenges pertaining to conflicting attributes such as activity, hemolysis, and toxicity have significantly impeded the progress of researchers. This paper introduces a paradigm shift by considering multiple attributes in AMP design. Presented herein is a novel approach termed Hypervolume-driven Multi-objective Antimicrobial Peptide Design (HMAMP), which prioritizes the simultaneous optimization of multiple attributes of AMPs. By synergizing reinforcement learning and a gradient descent algorithm rooted in the hypervolume maximization concept, HMAMP effectively expands exploration space and mitigates the issue of pattern collapse. This method generates a wide array of prospective AMP candidates that strike a balance among diverse attributes. Furthermore, we pinpoint knee points along the Pareto front of these candidate AMPs. Empirical results across five benchmark models substantiate that HMAMP-designed AMPs exhibit competitive performance and heightened diversity. A detailed analysis of the helical structures and molecular dynamics simulations for ten potential candidate AMPs validates the superiority of HMAMP in the realm of multi-objective AMP design. The ability of HMAMP to systematically craft AMPs considering multiple attributes marks a pioneering milestone, establishing a universal computational framework for the multi-objective design of AMPs.