Jiahua Rao

Jiahua Rao, Shuangjia Zheng, Sijie Mai et al.

Illuminating the interconnections between drugs and genes is an important topic in drug development and precision medicine. Currently, computational predictions of drug-gene interactions mainly focus on the binding interactions without considering other relation types like agonist, antagonist, etc. In addition, existing methods either heavily rely on high-quality domain features or are intrinsically transductive, which limits the capacity of models to generalize to drugs/genes that lack external information or are unseen during the training process. To address these problems, we propose a novel Communicative Subgraph representation learning for Multi-relational Inductive drug-Gene interactions prediction (CoSMIG), where the predictions of drug-gene relations are made through subgraph patterns, and thus are naturally inductive for unseen drugs/genes without retraining or utilizing external domain features. Moreover, the model strengthened the relations on the drug-gene graph through a communicative message passing mechanism. To evaluate our method, we compiled two new benchmark datasets from DrugBank and DGIdb. The comprehensive experiments on the two datasets showed that our method outperformed state-of-the-art baselines in the transductive scenarios and achieved superior performance in the inductive ones. Further experimental analysis including LINCS experimental validation and literature verification also demonstrated the value of our model.

Jiahua Rao, Zifei Shan, Longpo Liu et al.

With the recent progress in large-scale vision and language representation learning, Vision Language Pre-training (VLP) models have achieved promising improvements on various multi-modal downstream tasks. Albeit powerful, these models have not fully leveraged world knowledge to their advantage. A key challenge of knowledge-augmented VLP is the lack of clear connections between knowledge and multi-modal data. Moreover, not all knowledge present in images/texts is useful, therefore prior approaches often struggle to effectively integrate knowledge, visual, and textual information. In this study, we propose REtrieval-based knowledge Augmented Vision Language (REAVL), a novel knowledge-augmented pre-training framework to address the above issues. For the first time, we introduce a knowledge-aware self-supervised learning scheme that efficiently establishes the correspondence between knowledge and multi-modal data and identifies informative knowledge to improve the modeling of alignment and interactions between visual and textual modalities. By adaptively integrating informative knowledge with visual and textual information, REAVL achieves new state-of-the-art performance uniformly on knowledge-based vision-language understanding and multi-modal entity linking tasks, as well as competitive results on general vision-language tasks while only using 0.2% pre-training data of the best models. Our model shows strong sample efficiency and effective knowledge utilization.

Xichen Sun, Wentao Wei, Jiahua Rao et al.

Molecular structure generation from mass spectrometry is fundamental for understanding cellular metabolism and discovering novel compounds. Although tandem mass spectrometry (MS/MS) enables the high-throughput acquisition of fragment fingerprints, these spectra often reflect higher-order interactions involving the concerted cleavage of multiple atoms and bonds-crucial for resolving complex isomers and non-local fragmentation mechanisms. However, most existing methods adopt atom-centric and pairwise interaction modeling, overlooking higher-order edge interactions and lacking the capacity to systematically capture essential many-body characteristics for structure generation. To overcome these limitations, we present MBGen, a Many-Body enhanced diffusion framework for de novo molecular structure Generation from mass spectra. By integrating a many-body attention mechanism and higher-order edge modeling, MBGen comprehensively leverages the rich structural information encoded in MS/MS spectra, enabling accurate de novo generation and isomer differentiation for novel molecules. Experimental results on the NPLIB1 and MassSpecGym benchmarks demonstrate that MBGen achieves superior performance, with improvements of up to 230% over state-of-the-art methods, highlighting the scientific value and practical utility of many-body modeling for mass spectrometry-based molecular generation. Further analysis and ablation studies show that our approach effectively captures higher-order interactions and exhibits enhanced sensitivity to complex isomeric and non-local fragmentation information.

Anjie Qiao, Zhen Wang, Yaliang Li et al.

Virtual screening aims to efficiently identify active ligands from massive chemical libraries for a given target pocket. Recent CLIP-style models such as DrugCLIP enable scalable virtual screening by embedding pockets and ligands into a shared space. However, our analyses indicate that such representations can be insensitive to fine-grained binding interactions and may rely on shortcut correlations in training data, limiting their ability to rank ligands by true binding compatibility. To address these issues, we propose BindCLIP, a unified contrastive-generative representation learning framework for virtual screening. BindCLIP jointly trains pocket and ligand encoders using CLIP-style contrastive learning together with a pocket-conditioned diffusion objective for binding pose generation, so that pose-level supervision directly shapes the retrieval embedding space toward interaction-relevant features. To further mitigate shortcut reliance, we introduce hard-negative augmentation and a ligand-ligand anchoring regularizer that prevents representation collapse. Experiments on two public benchmarks demonstrate consistent improvements over strong baselines. BindCLIP achieves substantial gains on challenging out-of-distribution virtual screening and improves ligand-analogue ranking on the FEP+ benchmark. Together, these results indicate that integrating generative, pose-level supervision with contrastive learning yields more interaction-aware embeddings and improves generalization in realistic screening settings, bringing virtual screening closer to real-world applicability.

Jiahua Rao, Shuangjia Zheng, Yuedong Yang

Advances in machine learning have led to graph neural network-based methods for drug discovery, yielding promising results in molecular design, chemical synthesis planning, and molecular property prediction. However, current graph neural networks (GNNs) remain of limited acceptance in drug discovery is limited due to their lack of interpretability. Although this major weakness has been mitigated by the development of explainable artificial intelligence (XAI) techniques, the "ground truth" assignment in most explainable tasks ultimately rests with subjective judgments by humans so that the quality of model interpretation is hard to evaluate in quantity. In this work, we first build three levels of benchmark datasets to quantitatively assess the interpretability of the state-of-the-art GNN models. Then we implemented recent XAI methods in combination with different GNN algorithms to highlight the benefits, limitations, and future opportunities for drug discovery. As a result, GradInput and IG generally provide the best model interpretability for GNNs, especially when combined with GraphNet and CMPNN. The integrated and developed XAI package is fully open-sourced and can be used by practitioners to train new models on other drug discovery tasks.

Jiahua Rao, Jiancong Xie, Hanjing Lin et al.

Graph Neural Networks (GNNs) have gained considerable traction for their capability to effectively process topological data, yet their interpretability remains a critical concern. Current interpretation methods are dominated by post-hoc explanations to provide a transparent and intuitive understanding of GNNs. However, they have limited performance in interpreting complicated subgraphs and can't utilize the explanation to advance GNN predictions. On the other hand, transparent GNN models are proposed to capture critical subgraphs. While such methods could improve GNN predictions, they usually don't perform well on explanations. Thus, it is desired for a new strategy to better couple GNN explanation and prediction. In this study, we have developed a novel interpretable causal GNN framework that incorporates retrieval-based causal learning with Graph Information Bottleneck (GIB) theory. The framework could semi-parametrically retrieve crucial subgraphs detected by GIB and compress the explanatory subgraphs via a causal module. The framework was demonstrated to consistently outperform state-of-the-art methods, and to achieve 32.71\% higher precision on real-world explanation scenarios with diverse explanation types. More importantly, the learned explanations were shown able to also improve GNN prediction performance.

Anjie Qiao, Junjie Xie, Weifeng Huang et al.

Molecular optimization, aimed at improving binding affinity or other molecular properties, is a crucial task in drug discovery that often relies on the expertise of medicinal chemists. Recently, deep learning-based 3D generative models showed promise in enhancing the efficiency of molecular optimization. However, these models often struggle to adequately consider binding affinities with protein targets during lead optimization. Herein, we propose a 3D pocket-aware and affinity-guided diffusion model, named Diffleop, to optimize molecules with enhanced binding affinity. The model explicitly incorporates the knowledge of protein-ligand binding affinity to guide the denoising sampling for molecule generation with high affinity. The comprehensive evaluations indicated that Diffleop outperforms baseline models across multiple metrics, especially in terms of binding affinity.

Runjie Zheng, Zhen Wang, Anjie Qiao et al.

Accurate protein function prediction requires integrating heterogeneous intrinsic signals (e.g., sequence and structure) with noisy extrinsic contexts (e.g., protein-protein interactions and GO term annotations). However, two key challenges hinder effective fusion: (i) cross-modal distributional mismatch among embeddings produced by pre-trained intrinsic encoders, and (ii) noisy relational graphs of extrinsic data that degrade GNN-based information aggregation. We propose Diffused and Aligned Multi-modal Protein Embedding (DAMPE), a unified framework that addresses these through two core mechanisms. First, we propose Optimal Transport (OT)-based representation alignment that establishes correspondence between intrinsic embedding spaces of different modalities, effectively mitigating cross-modal heterogeneity. Second, we develop a Conditional Graph Generation (CGG)-based information fusion method, where a condition encoder fuses the aligned intrinsic embeddings to provide informative cues for graph reconstruction. Meanwhile, our theoretical analysis implies that the CGG objective drives this condition encoder to absorb graph-aware knowledge into its produced protein representations. Empirically, DAMPE outperforms or matches state-of-the-art methods such as DPFunc on standard GO benchmarks, achieving AUPR gains of 0.002-0.013 pp and Fmax gains 0.004-0.007 pp. Ablation studies further show that OT-based alignment contributes 0.043-0.064 pp AUPR, while CGG-based fusion adds 0.005-0.111 pp Fmax. Overall, DAMPE offers a scalable and theoretically grounded approach for robust multi-modal protein representation learning, substantially enhancing protein function prediction.

Zhongyue Zhang, Jiahua Rao, Jie Zhong et al.

Most human proteins remain undrugged, over 96% of human proteins remain unexploited by approved therapeutics. While structure-based virtual screening promises to expand the druggable proteome, existing methods lack atomic-level precision and fail to predict binding fitness, limiting translational impact. We present AuroBind, a scalable virtual screening framework that fine-tunes a custom atomic-level structural model on million-scale chemogenomic data. AuroBind integrates direct preference optimization, self-distillation from high-confidence complexes, and a teacher-student acceleration strategy to jointly predict ligand-bound structures and binding fitness. The proposed models outperform state-of-the-art models on structural and functional benchmarks while enabling 100,000-fold faster screening across ultra-large compound libraries. In a prospective screen across ten disease-relevant targets, AuroBind achieved experimental hit rates of 7-69%, with top compounds reaching sub-nanomolar to picomolar potency. For the orphan GPCRs GPR151 and GPR160, AuroBind identified both agonists and antagonists with success rates of 16-30%, and functional assays confirmed GPR160 modulation in liver and prostate cancer models. AuroBind offers a generalizable framework for structure-function learning and high-throughput molecular screening, bridging the gap between structure prediction and therapeutic discovery.

Jianwen Chen, Shuangjia Zheng, Ying Song et al.

Constructing appropriate representations of molecules lies at the core of numerous tasks such as material science, chemistry and drug designs. Recent researches abstract molecules as attributed graphs and employ graph neural networks (GNN) for molecular representation learning, which have made remarkable achievements in molecular graph modeling. Albeit powerful, current models either are based on local aggregation operations and thus miss higher-order graph properties or focus on only node information without fully using the edge information. For this sake, we propose a Communicative Message Passing Transformer (CoMPT) neural network to improve the molecular graph representation by reinforcing message interactions between nodes and edges based on the Transformer architecture. Unlike the previous transformer-style GNNs that treat molecules as fully connected graphs, we introduce a message diffusion mechanism to leverage the graph connectivity inductive bias and reduce the message enrichment explosion. Extensive experiments demonstrated that the proposed model obtained superior performances (around 4$\%$ on average) against state-of-the-art baselines on seven chemical property datasets (graph-level tasks) and two chemical shift datasets (node-level tasks). Further visualization studies also indicated a better representation capacity achieved by our model.

Shuangjia Zheng, Jiahua Rao, Zhongyue Zhang et al.

Synthesis planning is the process of recursively decomposing target molecules into available precursors. Computer-aided retrosynthesis can potentially assist chemists in designing synthetic routes, but at present it is cumbersome and provides results of dissatisfactory quality. In this study, we develop a template-free self-corrected retrosynthesis predictor (SCROP) to perform a retrosynthesis prediction task trained by using the Transformer neural network architecture. In the method, the retrosynthesis planning is converted as a machine translation problem between molecular linear notations of reactants and the products. Coupled with a neural network-based syntax corrector, our method achieves an accuracy of 59.0% on a standard benchmark dataset, which increases >21% over other deep learning methods, and >6% over template-based methods. More importantly, our method shows an accuracy 1.7 times higher than other state-of-the-art methods for compounds not appearing in the training set.