Tingjun Hou

Yiheng Zhu, Jialu Wu, Chaowen Hu et al.

Many crucial scientific problems involve designing novel molecules with desired properties, which can be formulated as a black-box optimization problem over the discrete chemical space. In practice, multiple conflicting objectives and costly evaluations (e.g., wet-lab experiments) make the diversity of candidates paramount. Computational methods have achieved initial success but still struggle with considering diversity in both objective and search space. To fill this gap, we propose a multi-objective Bayesian optimization (MOBO) algorithm leveraging the hypernetwork-based GFlowNets (HN-GFN) as an acquisition function optimizer, with the purpose of sampling a diverse batch of candidate molecular graphs from an approximate Pareto front. Using a single preference-conditioned hypernetwork, HN-GFN learns to explore various trade-offs between objectives. We further propose a hindsight-like off-policy strategy to share high-performing molecules among different preferences in order to speed up learning for HN-GFN. We empirically illustrate that HN-GFN has adequate capacity to generalize over preferences. Moreover, experiments in various real-world MOBO settings demonstrate that our framework predominantly outperforms existing methods in terms of candidate quality and sample efficiency. The code is available at https://github.com/violet-sto/HN-GFN.

Haitao Lin, Yufei Huang, Odin Zhang et al.

Generating molecules that bind to specific proteins is an important but challenging task in drug discovery. Previous works usually generate atoms in an auto-regressive way, where element types and 3D coordinates of atoms are generated one by one. However, in real-world molecular systems, the interactions among atoms in an entire molecule are global, leading to the energy function pair-coupled among atoms. With such energy-based consideration, the modeling of probability should be based on joint distributions, rather than sequentially conditional ones. Thus, the unnatural sequentially auto-regressive modeling of molecule generation is likely to violate the physical rules, thus resulting in poor properties of the generated molecules. In this work, a generative diffusion model for molecular 3D structures based on target proteins as contextual constraints is established, at a full-atom level in a non-autoregressive way. Given a designated 3D protein binding site, our model learns the generative process that denoises both element types and 3D coordinates of an entire molecule, with an equivariant network. Experimentally, the proposed method shows competitive performance compared with prevailing works in terms of high affinity with proteins and appropriate molecule sizes as well as other drug properties such as drug-likeness of the generated molecules.

Zipeng Zhong, Jie Song, Zunlei Feng et al.

Chemical reaction prediction, involving forward synthesis and retrosynthesis prediction, is a fundamental problem in organic synthesis. A popular computational paradigm formulates synthesis prediction as a sequence-to-sequence translation problem, where the typical SMILES is adopted for molecule representations. However, the general-purpose SMILES neglects the characteristics of chemical reactions, where the molecular graph topology is largely unaltered from reactants to products, resulting in the suboptimal performance of SMILES if straightforwardly applied. In this article, we propose the root-aligned SMILES (R-SMILES), which specifies a tightly aligned one-to-one mapping between the product and the reactant SMILES for more efficient synthesis prediction. Due to the strict one-to-one mapping and reduced edit distance, the computational model is largely relieved from learning the complex syntax and dedicated to learning the chemical knowledge for reactions. We compare the proposed R-SMILES with various state-of-the-art baselines and show that it significantly outperforms them all, demonstrating the superiority of the proposed method.

Zipeng Zhong, Jie Song, Zunlei Feng et al.

Retrosynthesis is the cornerstone of organic chemistry, providing chemists in material and drug manufacturing access to poorly available and brand-new molecules. Conventional rule-based or expert-based computer-aided synthesis has obvious limitations, such as high labor costs and limited search space. In recent years, dramatic breakthroughs driven by artificial intelligence have revolutionized retrosynthesis. Here we aim to present a comprehensive review of recent advances in AI-based retrosynthesis. For single-step and multi-step retrosynthesis both, we first list their goal and provide a thorough taxonomy of existing methods. Afterwards, we analyze these methods in terms of their mechanism and performance, and introduce popular evaluation metrics for them, in which we also provide a detailed comparison among representative methods on several public datasets. In the next part we introduce popular databases and established platforms for retrosynthesis. Finally, this review concludes with a discussion about promising research directions in this field.

Yue Wan, Jialu Wu, Tingjun Hou et al.

Reliable molecular property prediction is essential for various scientific endeavors and industrial applications, such as drug discovery. However, the data scarcity, combined with the highly non-linear causal relationships between physicochemical and biological properties and conventional molecular featurization schemes, complicates the development of robust molecular machine learning models. Self-supervised learning (SSL) has emerged as a popular solution, utilizing large-scale, unannotated molecular data to learn a foundational representation of chemical space that might be advantageous for downstream tasks. Yet, existing molecular SSL methods largely overlook chemical knowledge, including molecular structure similarity, scaffold composition, and the context-dependent aspects of molecular properties when operating over the chemical space. They also struggle to learn the subtle variations in structure-activity relationship. This paper introduces a novel pre-training framework that learns robust and generalizable chemical knowledge. It leverages the structural hierarchy within the molecule, embeds them through distinct pre-training tasks across channels, and aggregates channel information in a task-specific manner during fine-tuning. Our approach demonstrates competitive performance across various molecular property benchmarks and offers strong advantages in particularly challenging yet ubiquitous scenarios like activity cliffs.

Jike Wang, Rui Qin, Mingyang Wang et al.

Significant interests have recently risen in leveraging sequence-based large language models (LLMs) for drug design. However, most current applications of LLMs in drug discovery lack the ability to comprehend three-dimensional (3D) structures, thereby limiting their effectiveness in tasks that explicitly involve molecular conformations. In this study, we introduced Token-Mol, a token-only 3D drug design model. This model encodes all molecular information, including 2D and 3D structures, as well as molecular property data, into tokens, which transforms classification and regression tasks in drug discovery into probabilistic prediction problems, thereby enabling learning through a unified paradigm. Token-Mol is built on the transformer decoder architecture and trained using random causal masking techniques. Additionally, we proposed the Gaussian cross-entropy (GCE) loss function to overcome the challenges in regression tasks, significantly enhancing the capacity of LLMs to learn continuous numerical values. Through a combination of fine-tuning and reinforcement learning (RL), Token-Mol achieves performance comparable to or surpassing existing task-specific methods across various downstream tasks, including pocket-based molecular generation, conformation generation, and molecular property prediction. Compared to existing molecular pre-trained models, Token-Mol exhibits superior proficiency in handling a wider range of downstream tasks essential for drug design. Notably, our approach improves regression task accuracy by approximately 30% compared to similar token-only methods. Token-Mol overcomes the precision limitations of token-only models and has the potential to integrate seamlessly with general models such as ChatGPT, paving the way for the development of a universal artificial intelligence drug design model that facilitates rapid and high-quality drug design by experts.

Mingze Yin, Hanjing Zhou, Yiheng Zhu et al.

Proteins govern most biological functions essential for life, but achieving controllable protein discovery and optimization remains challenging. Recently, machine learning-assisted protein editing (MLPE) has shown promise in accelerating optimization cycles and reducing experimental workloads. However, current methods struggle with the vast combinatorial space of potential protein edits and cannot explicitly conduct protein editing using biotext instructions, limiting their interactivity with human feedback. To fill these gaps, we propose a novel method called ProtET for efficient CLIP-informed protein editing through multi-modality learning. Our approach comprises two stages: in the pretraining stage, contrastive learning aligns protein-biotext representations encoded by two large language models (LLMs), respectively. Subsequently, during the protein editing stage, the fused features from editing instruction texts and original protein sequences serve as the final editing condition for generating target protein sequences. Comprehensive experiments demonstrated the superiority of ProtET in editing proteins to enhance human-expected functionality across multiple attribute domains, including enzyme catalytic activity, protein stability and antibody specific binding ability. And ProtET improves the state-of-the-art results by a large margin, leading to significant stability improvements of 16.67% and 16.90%. This capability positions ProtET to advance real-world artificial protein editing, potentially addressing unmet academic, industrial, and clinical needs.

Shi Li, Xujun Zhang, Mingquan Liu et al.

Nucleic acids are increasingly recognized as therapeutic targets beyond conventional protein-centered drug discovery, yet accurate and efficient docking of small molecules to nucleic acid structures remains challenging. Physics-based docking methods often show limited accuracy and efficiency, whereas deep learning approaches are constrained by the scarcity of experimentally resolved nucleic acid-ligand complexes. Here, we present NucleoDock, a deep learning framework for nucleic acid-small molecule docking. To address data scarcity, NucleoDock combines physics-guided large-scale pretraining on millions of docking-generated synthetic complexes with fine-tuning on curated experimental co-crystal structures. It further integrates sequence- and structure-informed nucleotide representations with atomistic three-dimensional features to capture both biological context and binding-site geometry. A mixture density network-based geometric scoring head is used to model conditional interaction-distance distributions for pose ranking. On an external benchmark of 125 nucleic acid-ligand complexes, NucleoDock achieved a top-1 success rate of 56 percent at an RMSD cutoff of 2.0 Angstrom, outperforming rDock with 29 percent, while generating 100 poses in approximately 5 seconds per complex. Retrospective virtual screening on the ROBIN benchmark further showed improved early enrichment. NucleoDock represents a step toward bridging the methodological gap between protein- and nucleic acid-directed computational drug discovery.

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.

Yiheng Zhu, Zhenqiu Ouyang, Ben Liao et al.

Molecular de novo design is a critical yet challenging task in scientific fields, aiming to design novel molecular structures with desired property profiles. Significant progress has been made by resorting to generative models for graphs. However, limited attention is paid to hierarchical generative models, which can exploit the inherent hierarchical structure (with rich semantic information) of the molecular graphs and generate complex molecules of larger size that we shall demonstrate to be difficult for most existing models. The primary challenge to hierarchical generation is the non-differentiable issue caused by the generation of intermediate discrete coarsened graph structures. To sidestep this issue, we cast the tricky hierarchical generation problem over discrete spaces as the reverse process of hierarchical representation learning and propose MolHF, a new hierarchical flow-based model that generates molecular graphs in a coarse-to-fine manner. Specifically, MolHF first generates bonds through a multi-scale architecture, then generates atoms based on the coarsened graph structure at each scale. We demonstrate that MolHF achieves state-of-the-art performance in random generation and property optimization, implying its high capacity to model data distribution. Furthermore, MolHF is the first flow-based model that can be applied to model larger molecules (polymer) with more than 100 heavy atoms. The code and models are available at https://github.com/violet-sto/MolHF.

Odin Zhang, Haitao Lin, Hui Zhang et al.

The idea of using deep-learning-based molecular generation to accelerate discovery of drug candidates has attracted extraordinary attention, and many deep generative models have been developed for automated drug design, termed molecular generation. In general, molecular generation encompasses two main strategies: de novo design, which generates novel molecular structures from scratch, and lead optimization, which refines existing molecules into drug candidates. Among them, lead optimization plays an important role in real-world drug design. For example, it can enable the development of me-better drugs that are chemically distinct yet more effective than the original drugs. It can also facilitate fragment-based drug design, transforming virtual-screened small ligands with low affinity into first-in-class medicines. Despite its importance, automated lead optimization remains underexplored compared to the well-established de novo generative models, due to its reliance on complex biological and chemical knowledge. To bridge this gap, we conduct a systematic review of traditional computational methods for lead optimization, organizing these strategies into four principal sub-tasks with defined inputs and outputs. This review delves into the basic concepts, goals, conventional CADD techniques, and recent advancements in AIDD. Additionally, we introduce a unified perspective based on constrained subgraph generation to harmonize the methodologies of de novo design and lead optimization. Through this lens, de novo design can incorporate strategies from lead optimization to address the challenge of generating hard-to-synthesize molecules; inversely, lead optimization can benefit from the innovations in de novo design by approaching it as a task of generating molecules conditioned on certain substructures.

Yiheng Zhu, Zitai Kong, Jialu Wu et al.

The design of novel protein sequences with targeted functionalities underpins a central theme in protein engineering, impacting diverse fields such as drug discovery and enzymatic engineering. However, navigating this vast combinatorial search space remains a severe challenge due to time and financial constraints. This scenario is rapidly evolving as the transformative advancements in AI, particularly in the realm of generative models and optimization algorithms, have been propelling the protein design field towards an unprecedented revolution. In this survey, we systematically review recent advances in generative AI for controllable protein sequence design. To set the stage, we first outline the foundational tasks in protein sequence design in terms of the constraints involved and present key generative models and optimization algorithms. We then offer in-depth reviews of each design task and discuss the pertinent applications. Finally, we identify the unresolved challenges and highlight research opportunities that merit deeper exploration.

Odin Zhang, Yufei Huang, Shichen Cheng et al.

Most earlier 3D structure-based molecular generation approaches follow an atom-wise paradigm, incrementally adding atoms to a partially built molecular fragment within protein pockets. These methods, while effective in designing tightly bound ligands, often overlook other essential properties such as synthesizability. The fragment-wise generation paradigm offers a promising solution. However, a common challenge across both atom-wise and fragment-wise methods lies in their limited ability to co-design plausible chemical and geometrical structures, resulting in distorted conformations. In response to this challenge, we introduce the Deep Geometry Handling protocol, a more abstract design that extends the design focus beyond the model architecture. Through a comprehensive review of existing geometry-related models and their protocols, we propose a novel hybrid strategy, culminating in the development of FragGen - a geometry-reliable, fragment-wise molecular generation method. FragGen marks a significant leap forward in the quality of generated geometry and the synthesis accessibility of molecules. The efficacy of FragGen is further validated by its successful application in designing type II kinase inhibitors at the nanomolar level.

Zitai Kong, Yiheng Zhu, Yinlong Xu et al.

The design of protein sequences with desired functionalities is a fundamental task in protein engineering. Deep generative methods, such as autoregressive models and diffusion models, have greatly accelerated the discovery of novel protein sequences. However, these methods mainly focus on local or shallow residual semantics and suffer from low inference efficiency, large modeling space and high training cost. To address these challenges, we introduce ProtFlow, a fast flow matching-based protein sequence design framework that operates on embeddings derived from semantically meaningful latent space of protein language models. By compressing and smoothing the latent space, ProtFlow enhances performance while training on limited computational resources. Leveraging reflow techniques, ProtFlow enables high-quality single-step sequence generation. Additionally, we develop a joint design pipeline for the design scene of multichain proteins. We evaluate ProtFlow across diverse protein design tasks, including general peptides and long-chain proteins, antimicrobial peptides, and antibodies. Experimental results demonstrate that ProtFlow outperforms task-specific methods in these applications, underscoring its potential and broad applicability in computational protein sequence design and analysis.

Mingze Yin, Hanjing Zhou, Jialu Wu et al.

Antibodies safeguard our health through their precise and potent binding to specific antigens, demonstrating promising therapeutic efficacy in the treatment of numerous diseases, including COVID-19. Recent advancements in biomedical language models have shown the great potential to interpret complex biological structures and functions. However, existing antibody specific models have a notable limitation that they lack explicit consideration for antibody structural information, despite the fact that both 1D sequence and 3D structure carry unique and complementary insights into antibody behavior and functionality. This paper proposes Sequence-Structure multi-level pre-trained Antibody Language Model (S$^2$ALM), combining holistic sequential and structural information in one unified, generic antibody foundation model. We construct a hierarchical pre-training paradigm incorporated with two customized multi-level training objectives to facilitate the modeling of comprehensive antibody representations. S$^2$ALM's representation space uncovers inherent functional binding mechanisms, biological evolution properties and structural interaction patterns. Pre-trained over 75 million sequences and 11.7 million structures, S$^2$ALM can be adopted for diverse downstream tasks: accurately predicting antigen-antibody binding affinities, precisely distinguishing B cell maturation stages, identifying antibody crucial binding positions, and specifically designing novel coronavirus-binding antibodies. Remarkably, S$^2$ALM outperforms well-established and renowned baselines and sets new state-of-the-art performance across extensive antibody specific understanding and generation tasks. S$^2$ALM's ability to model comprehensive and generalized representations further positions its potential to advance real-world therapeutic antibody development, potentially addressing unmet academic, industrial, and clinical needs.

Yuchen Zhu, Jihong Chen, Yitong Li et al.

Structural assessment of biomolecular complexes is vital for translating molecular models into functional insights, shaping our understanding of biology and aiding drug discovery. However, current structure-based scoring functions often lack generalizability across diverse biomolecular systems. We present BioScore, a foundational scoring function that addresses key challenges -- data sparsity, cross-system representation, and task compatibility -- through a dual-scale geometric graph learning framework with tailored modules for structure assessment and affinity prediction. BioScore supports a wide range of tasks, including affinity prediction, conformation ranking, and structure-based virtual screening. Evaluated on 16 benchmarks spanning proteins, nucleic acids, small molecules, and carbohydrates, BioScore consistently outperforms or matches 70 traditional and deep learning methods. Our newly proposed PPI Benchmark further enables comprehensive evaluation of protein-protein complex scoring. BioScore demonstrates broad applicability: (1) pretraining on mixed-structure data boosts protein-protein affinity prediction by up to 40% and antigen-antibody binding correlation by over 90%; (2) cross-system generalizability enables zero- and few-shot prediction with up to 71% correlation gain; and (3) its unified representation captures chemically challenging systems such as cyclic peptides, improving affinity prediction by over 60%. BioScore establishes a robust and generalizable framework for structural assessment across complex biomolecular landscapes.

Qun Su, Kai Zhu, Qiaolin Gou et al.

Accurate atomistic biomolecular simulations are vital for disease mechanism understanding, drug discovery, and biomaterial design, but existing simulation methods exhibit significant limitations. Classical force fields are efficient but lack accuracy for transition states and fine conformational details critical in many chemical and biological processes. Quantum Mechanics (QM) methods are highly accurate but computationally infeasible for large-scale or long-time simulations. AI-based force fields (AIFFs) aim to achieve QM-level accuracy with efficiency but struggle to balance many-body modeling complexity, accuracy, and speed, often constrained by limited training data and insufficient validation for generalizability. To overcome these challenges, we introduce LiTEN, a novel equivariant neural network with Tensorized Quadrangle Attention (TQA). TQA efficiently models three- and four-body interactions with linear complexity by reparameterizing high-order tensor features via vector operations, avoiding costly spherical harmonics. Building on LiTEN, LiTEN-FF is a robust AIFF foundation model, pre-trained on the extensive nablaDFT dataset for broad chemical generalization and fine-tuned on SPICE for accurate solvated system simulations. LiTEN achieves state-of-the-art (SOTA) performance across most evaluation subsets of rMD17, MD22, and Chignolin, outperforming leading models such as MACE, NequIP, and EquiFormer. LiTEN-FF enables the most comprehensive suite of downstream biomolecular modeling tasks to date, including QM-level conformer searches, geometry optimization, and free energy surface construction, while offering 10x faster inference than MACE-OFF for large biomolecules (~1000 atoms). In summary, we present a physically grounded, highly efficient framework that advances complex biomolecular modeling, providing a versatile foundation for drug discovery and related applications.

Lijun Liu, Jiali Yang, Jianfei Song et al.

Recombinant adeno-associated virus (rAAV) vectors have revolutionized gene therapy, but their broad tropism and suboptimal transduction efficiency limit their clinical applications. To overcome these limitations, researchers have focused on designing and screening capsid libraries to identify improved vectors. However, the large sequence space and limited resources present challenges in identifying viable capsid variants. In this study, we propose an end-to-end diffusion model to generate capsid sequences with enhanced viability. Using publicly available AAV2 data, we generated 38,000 diverse AAV2 viral protein (VP) sequences, and evaluated 8,000 for viral selection. The results attested the superiority of our model compared to traditional methods. Additionally, in the absence of AAV9 capsid data, apart from one wild-type sequence, we used the same model to directly generate a number of viable sequences with up to 9 mutations. we transferred the remaining 30,000 samples to the AAV9 domain. Furthermore, we conducted mutagenesis on AAV9 VP hypervariable regions VI and V, contributing to the continuous improvement of the AAV9 VP sequence. This research represents a significant advancement in the design and functional validation of rAAV vectors, offering innovative solutions to enhance specificity and transduction efficiency in gene therapy applications.

Hongyan Du, Guo-Wei Wei, Tingjun Hou

The escalating drug addiction crisis in the United States underscores the urgent need for innovative therapeutic strategies. This study embarked on an innovative and rigorous strategy to unearth potential drug repurposing candidates for opioid and cocaine addiction treatment, bridging the gap between transcriptomic data analysis and drug discovery. We initiated our approach by conducting differential gene expression analysis on addiction-related transcriptomic data to identify key genes. We propose a novel topological differentiation to identify key genes from a protein-protein interaction (PPI) network derived from DEGs. This method utilizes persistent Laplacians to accurately single out pivotal nodes within the network, conducting this analysis in a multiscale manner to ensure high reliability. Through rigorous literature validation, pathway analysis, and data-availability scrutiny, we identified three pivotal molecular targets, mTOR, mGluR5, and NMDAR, for drug repurposing from DrugBank. We crafted machine learning models employing two natural language processing (NLP)-based embeddings and a traditional 2D fingerprint, which demonstrated robust predictive ability in gauging binding affinities of DrugBank compounds to selected targets. Furthermore, we elucidated the interactions of promising drugs with the targets and evaluated their drug-likeness. This study delineates a multi-faceted and comprehensive analytical framework, amalgamating bioinformatics, topological data analysis and machine learning, for drug repurposing in addiction treatment, setting the stage for subsequent experimental validation. The versatility of the methods we developed allows for applications across a range of diseases and transcriptomic datasets.