Drug synergy prediction is a critical task in the development of effective combination therapies for complex diseases, including cancer . Although existing methods have shown promising results, they often operate as black-box predictors that rely predominantly on statistical correlations between drug characteristics and results. T o address this limitation, we propose CausalDDS, a novel framework that disentangles drug molecules into causal and spurious substructures, utilizing the causal substructure representations for predicting drug synergy. By focusing on causal sub-structures, CausalDDS effectively mitigates the impact of redundant features introduced by spurious substructures, enhancing the accuracy and interpretability of the model. In addition, CausalDDS employs a conditional intervention mechanism, where interventions are conditioned on paired molecular structures, and introduces a novel optimization objective guided by the principles of sufficiency and independence. Extensive experiments demonstrate that our method outperforms baseline models, particularly in cold start and out-of-distribution settings. Besides, CausalDDS effectively identifies key substructures underlying drug synergy, providing clear insights into how drug combinations work at the molecular level. These results underscore the potential of CausalDDS as a practical tool for predicting drug synergy and facilitating drug discovery.

Our algorithm can well transfer the knowledge gained in single-target pretraining to dual-target scenarios in a zero-shot manner.

Drug combinations are essential in cancer therapy, leveraging synergistic drug-drug interactions (DDI) to enhance efficacy and combat resistance. However, the vast combinatorial space makes experimental screening impractical, and existing computational models struggle to capture the complex, bidirectional nature of DDIs, often relying on independent drug encoding or simplistic fusion strategies that miss fine-grained inter-molecular dynamics. Moreover, state-of-the-art graph-based approaches suffer from high computational costs, limiting scalability for real-world drug discovery. To address this, we propose DPASyn, a novel drug synergy prediction framework featuring a dual-attention mechanism and Precision-Aware Quantization (PAQ). The dual-attention architecture jointly models intra-drug structures and inter-drug interactions via shared projections and cross-drug attention, enabling fine-grained, biologically plausible synergy modeling. While this enhanced expressiveness brings increased computational resource consumption, our proposed PAQ strategy complements it by dynamically optimizing numerical precision during training based on feature sensitivity-reducing memory usage by 40% and accelerating training threefold without sacrificing accuracy. With LayerNorm-stabilized residual connections for training stability, DPASyn outperforms seven state-of-the-art methods on the O'Neil dataset (13,243 combinations) and supports full-batch processing of up to 256 graphs on a single GPU, setting a new standard for efficient and expressive drug synergy prediction.

Personalizing combination therapies in oncology requires navigating an immense space of possible drug and dose combinations, a task that remains largely infeasible through exhaustive experimentation. Recent developments in patient-derived models have enabled high-throughput ex vivo screening, but the number of feasible experiments is limited. Further, a tight therapeutic window makes gathering molecular profiling information (e.g. RNA-seq) impractical as a means of guiding drug response prediction. This leads to a challenging cold-start problem: how do we select the most informative combinations to test early, when no prior information about the patient is available? We propose a strategy that leverages a pretrained deep learning model built on historical drug response data. The model provides both embeddings for drug combinations and dose-level importance scores, enabling a principled selection of initial experiments. We combine clustering of drug embeddings to ensure functional diversity with a dose-weighting mechanism that prioritizes doses based on their historical informativeness. Retrospective simulations on large-scale drug combination datasets show that our method substantially improves initial screening efficiency compared to baselines, offering a viable path for more effective early-phase decision-making in personalized combination drug screens.

Background: Gastric neoplasm, primarily adenocarcinoma, is an aggressive cancer with high mortality, often diagnosed late, leading to complications like metastasis. Effective drug combinations are vital to address disease heterogeneity, enhance efficacy, reduce resistance, and improve patient outcomes. Methods: The RAIN method integrated Graph SAGE to propose drug combinations, using a graph model with p-value-weighted edges connecting drugs, genes, and proteins. NLP and systematic literature review (PubMed, Scopus, etc.) validated proposed drugs, followed by network meta-analysis to assess efficacy, implemented in Python. Results: Oxaliplatin, fluorouracil, and trastuzumab were identified as effective, supported by 61 studies. Fluorouracil alone had a p-value of 0.0229, improving to 0.0099 with trastuzumab, and 0.0069 for the triple combination, indicating superior efficacy. Conclusion: The RAIN method, combining AI and network meta-analysis, effectively identifies optimal drug combinations for gastric neoplasm, offering a promising strategy to enhance treatment outcomes and guide health policy.

It is well known that traditional drug discovery is costly, time-consuming, and with high failure rates [1]. To streamline the process of drug discovery and mitigate resource-intensive laboratory work, significant research has been dedicated to the development of computational methods. Existing literature provides some comprehensive reviews on deep learning approaches in drug discovery [2, 3, 4, 5]. In this review, we focus on the development and applications of Graph Neural Networks (GNNs) on three related areas of computational drug development, namely, Molecule Generation, Molecular Property Prediction, and Drug-Drug Interaction Prediction, which not only receive increasing attention but also show promising results. We will summarize some most recent developments in these research areas and focus on computational advances published since 2021.

Predicting clinical outcomes from preclinical data is essential for identifying safe and effective drug combinations. Current models rely on structural or target-based features to identify high-efficacy, low-toxicity drug combinations. However, these approaches fail to incorporate the multimodal data necessary for accurate, clinically-relevant predictions. Here, we introduce MADRIGAL, a multimodal AI model that learns from structural, pathway, cell viability, and transcriptomic data to predict drug combination effects across 953 clinical outcomes and 21842 compounds, including combinations of approved drugs and novel compounds in development. MADRIGAL uses a transformer bottleneck module to unify preclinical drug data modalities while handling missing data during training and inference--a major challenge in multimodal learning. It outperforms single-modality methods and state-of-the-art models in predicting adverse drug interactions. MADRIGAL performs virtual screening of anticancer drug combinations and supports polypharmacy management for type II diabetes and metabolic dysfunction-associated steatohepatitis (MASH). It identifies transporter-mediated drug interactions. MADRIGAL predicts resmetirom, the first and only FDA-approved drug for MASH, among therapies with the most favorable safety profile. It supports personalized cancer therapy by integrating genomic profiles from cancer patients. Using primary acute myeloid leukemia samples and patient-derived xenograft models, it predicts the efficacy of personalized drug combinations. Integrating MADRIGAL with a large language model allows users to describe clinical outcomes in natural language, improving safety assessment by identifying potential adverse interactions and toxicity risks. MADRIGAL provides a multimodal approach for designing combination therapies with improved predictive accuracy and clinical relevance.

Drug-side effect research is vital for understanding adverse reactions arising in complex multi-drug therapies. However, the scarcity of higher-order datasets that capture the combinatorial effects of multiple drugs severely limits progress in this field. Existing resources such as TWOSIDES primarily focus on pairwise interactions. To fill this critical gap, we introduce HODDI, the first Higher-Order Drug-Drug Interaction Dataset, constructed from U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) records spanning the past decade, to advance computational pharmacovigilance. HODDI contains 109,744 records involving 2,506 unique drugs and 4,569 unique side effects, specifically curated to capture multi-drug interactions and their collective impact on adverse effects. Comprehensive statistical analyses demonstrate HODDI's extensive coverage and robust analytical metrics, making it a valuable resource for studying higher-order drug relationships. Evaluating HODDI with multiple models, we found that simple Multi-Layer Perceptron (MLP) can outperform graph models, while hypergraph models demonstrate superior performance in capturing complex multi-drug interactions, further validating HODDI's effectiveness. Our findings highlight the inherent value of higher-order information in drug-side effect prediction and position HODDI as a benchmark dataset for advancing research in pharmacovigilance, drug safety, and personalized medicine. The dataset and codes are available at https://github.com/TIML-Group/HODDI.

Drug combination therapies have shown promising therapeutic efficacy in complex diseases and have demonstrated the potential to reduce drug resistance. However, the huge number of possible drug combinations makes it difficult to screen them all in traditional experiments. In this study, we proposed MD-Syn, a computational framework, which is based on the multidimensional feature fusion method and multi-head attention mechanisms. Given drug pair-cell line triplets, MD-Syn considers one-dimensional and two-dimensional feature spaces simultaneously. It consists of a one-dimensional feature embedding module (1D-FEM), a two-dimensional feature embedding module (2D-FEM), and a deep neural network-based classifier for synergistic drug combination prediction. MD-Syn achieved the AUROC of 0.919 in 5-fold cross-validation, outperforming the state-of-the-art methods. Further, MD-Syn showed comparable results over two independent datasets. In addition, the multi-head attention mechanisms not only learn embeddings from different feature aspects but also focus on essential interactive feature elements, improving the interpretability of MD-Syn. In summary, MD-Syn is an interpretable framework to prioritize synergistic drug combination pairs with chemicals and cancer cell line gene expression profiles. To facilitate broader community access to this model, we have developed a web portal (https://labyeh104-2.life.nthu.edu.tw/) that enables customized predictions of drug combination synergy effects based on user-specified compounds.