MOTIVATION: Rational molecule generation that balances binding affinity with favorable physicochemical properties remains a formidable challenge in structure-based drug design. The number of functional groups is a key determinant, as over-functionalization compromises physicochemical properties, whereas under-functionalization reduces binding affinity. However, current methods are limited in their capacity to incorporate the constraint. RESULTS: To address this, we present NumMolFormer, a Transformer-based framework designed to explicitly model functional group numbers. NumMolFormer adopts a dual-sequence input strategy, integrated with a numerical embedding module and a dual-stream differential attention mechanism, allowing molecular structures and functional group numbers to be encoded separately. This formulation alleviates the inherent limitations of standard Transformer in handling numerical information. In addition, we construct a large-scale dataset of 18 million molecules with functional group annotations for molecular pre-training, and further fine-tune the model using a combination of self-supervised learning and reinforcement learning under protein pocket constraints. The results demonstrate that NumMolFormer effectively leverages functional group information to generate molecules with improved binding affinity, synthetic accessibility, and drug-likeness compared to baseline methods. AVAILABILITY AND IMPLEMENTATION: The source code and datasets are available at http://www.github.com/zengzhicun/nummolformer.

Ion channels are critical targets in drug development and play an important role in the treatment of various diseases. However, existing prediction methods either generalize across all drug targets or focus narrowly on specific ion channel proteins, leading to limitations in accuracy and versatility. In this study, we propose DeepDICI, a novel deep learning framework that integrates topology-aware protein embeddings with spatial-channel interaction modeling to overcome these challenges. Our approach leverages a LLaMA3-style language model to capture longrange structural dependencies between transmembrane segments and cytoplasmic domains, effectively simulating the grammar of channel folding. In addition, a Cross-Attention network dynamically aligns drug substructures with channel functional domains, enabling the precise identification of state-dependent binding interfaces. Comprehensive evaluations in multiple scenarios demonstrate that DeepDICI achieves the highest precision of prediction$(P R C>0.98)$and maintains exceptional robustness under cold start conditions, showing a 28.9% improvement in terms of recall for novel chemical scaffolds and a 14.3% increase in terms of accuracy for unseen channel targets. All the results indicate that DeepDICI represents a unified and interpretable paradigm for ion channel-targeted drug discovery, bridging computational predictions with biophysical insights into structuredynamic protein systems. The code and datasets for DeepDICI are freely available at https://github.com/CSUBioGroup/DeepDICI.

Predicting the interaction of protein and compound is an important task in drug discovery. Molecular docking has been a fundamental and vital computer-aid tool for digging potential interaction of the protein-compound pair. With the recent great success of artificial intelligence (AI), the scoring function, as a fundamental part of molecular docking, has been achieving much better performance by incorporating AI-based models. However, the AI-based models usually focus on a single prediction task (e.g., affinity prediction), which is limited by their lack of extensibility. Moreover, the performance of AI-based models usually declines in cold start scenarios, thus compromising the robustness. To this end, we propose a novel deep learning-based graph model based on the transformer convolution network for pose scoring and affinity prediction. TransScore captures the intrinsic characteristics of protein-compound poses by employing the self-attention mechanism, which achieves superior performances in both cold and warm scenarios for the pose-scoring task. The outstanding performance is also shown in imbalanced datasets, which demonstrates the robustness of TransScore. In addition, the gated residual algorithm in TransScore enhances the model to adapt to diverse related tasks. In particular, in the affinity prediction task, we have observed consistent improvements in warm/cold start scenarios. Moreover, it is noticeable that TransScore excels in both accuracy and precision, accurately predicting affinities and their relative ordering. We also conducted an analysis on carbonic anhydrase II, which bears out that TransScore can elaborate the interaction mechanism of the protein-ligand pair, suggesting the potential application of TransScore in drug discovery.

MOTIVATION: Drug repositioning is an effective strategy to identify new indications for existing drugs, providing the quickest possible transition from bench to bedside. With the rapid development of deep learning, graph convolutional networks (GCNs) have been widely adopted for drug repositioning tasks. However, prior GCNs based methods exist limitations in deeply integrating node features and topological structures, which may hinder the capability of GCNs. RESULTS: In this study, we propose an adaptive GCNs approach, termed AdaDR, for drug repositioning by deeply integrating node features and topological structures. Distinct from conventional graph convolution networks, AdaDR models interactive information between them with adaptive graph convolution operation, which enhances the expression of model. Concretely, AdaDR simultaneously extracts embeddings from node features and topological structures and then uses the attention mechanism to learn adaptive importance weights of the embeddings. Experimental results show that AdaDR achieves better performance than multiple baselines for drug repositioning. Moreover, in the case study, exploratory analyses are offered for finding novel drug-disease associations. AVAILABILITY AND IMPLEMENTATION: The soure code of AdaDR is available at: https://github.com/xinliangSun/AdaDR.

MOTIVATION: The identification of compound-protein interactions (CPIs) is an essential step in the process of drug discovery. The experimental determination of CPIs is known for a large amount of funds and time it consumes. Computational model has therefore become a promising and efficient alternative for predicting novel interactions between compounds and proteins on a large scale. Most supervised machine learning prediction models are approached as a binary classification problem, which aim to predict whether there is an interaction between the compound and the protein or not. However, CPI is not a simple binary on-off relationship, but a continuous value reflects how tightly the compound binds to a particular target protein, also called binding affinity. RESULTS: In this study, we propose an end-to-end neural network model, called BACPI, to predict CPI and binding affinity. We employ graph attention network and convolutional neural network (CNN) to learn the representations of compounds and proteins and develop a bi-directional attention neural network model to integrate the representations. To evaluate the performance of BACPI, we use three CPI datasets and four binding affinity datasets in our experiments. The results show that, when predicting CPIs, BACPI significantly outperforms other available machine learning methods on both balanced and unbalanced datasets. This suggests that the end-to-end neural network model that predicts CPIs directly from low-level representations is more robust than traditional machine learning-based methods. And when predicting binding affinities, BACPI achieves higher performance on large datasets compared to other state-of-the-art deep learning methods. This comparison result suggests that the proposed method with bi-directional attention neural network can capture the important regions of compounds and proteins for binding affinity prediction. AVAILABILITY AND IMPLEMENTATION: Data and source codes are available at https://github.com/CSUBioGroup/BACPI.

BACKGROUND: Drug discovery is known for the large amount of money and time it consumes and the high risk it takes. Drug repositioning has, therefore, become a popular approach to save time and cost by finding novel indications for approved drugs. In order to distinguish these novel indications accurately in a great many of latent associations between drugs and diseases, it is necessary to exploit abundant heterogeneous information about drugs and diseases. RESULTS: In this article, we propose a meta-path-based computational method called NEDD to predict novel associations between drugs and diseases using heterogeneous information. First, we construct a heterogeneous network as an undirected graph by integrating drug-drug similarity, disease-disease similarity, and known drug-disease associations. NEDD uses meta paths of different lengths to explicitly capture the indirect relationships, or high order proximity, within drugs and diseases, by which the low dimensional representation vectors of drugs and diseases are obtained. NEDD then uses a random forest classifier to predict novel associations between drugs and diseases. CONCLUSIONS: The experiments on a gold standard dataset which contains 1933 validated drug-disease associations show that NEDD produces superior prediction results compared with the state-of-the-art approaches.

Identifying drug-target interactions (DTIs) is an important task in drug discovery. Various computational models have been proposed to predict potential association between drugs and targets. However, it is still a great challenge to accurately predict the potential drug-target interactions with rare known drug-target interactions. In this work, we propose a heterogeneous network embedding model to predict drug-target interactions, called HNEDTI. Based on the assumption that similar drugs share similar patterns of relationships with target proteins, we integrate the drug-drug similarity network, target-target similarity network and known drug-target interactions into a heterogeneous network. HNEDTI can learn more accurate feature representation of drugs and targets by extract both local and global information of the heterogeneous network from different lengths of meta-paths. The low dimensional feature representation vectors of drugs and targets are applied to random forest model to predict whether the given drug-target pair has an interaction. The evaluation on four benchmark datasets (Enzyme, Ion Channel, GPCR and Nuclear Receptor) shows that our method HNEDTI outperforms the previous methods.

Long non-coding RNAs (lncRNAs) are the foundation for understanding mechanisms of many human diseases. Considering the limited number of known experimentally verified associations between lncRNAs and diseases, it is appealing to develop accurate and effective computational methods to identify lncRNA-disease associations. Conventional matrix factorization-based methods cannot model complicated associations between lncRNAs and diseases. In this study, we propose a novel computational framework, through combining linear and non-linear features, which is used for lncRNA-disease association prediction. In our model, a conventional matrix factorization method is applied to extract linear features between lncRNAs and diseases. Deep learning techniques (fully connected layers) are applied to extract nonlinear features between lncRNAs and diseases. Finally, linear and non-linear features are fused to improve predictive performance. Compared to previous studies, our model can take advantages of the combination of linear and non-linear features between lncRNAs and diseases, and thus can effectively identify potential lncRNA-disease associations. The results show that our method achieves state-of-the-art performance in the leave-one-out cross-validation. The source codes of our method can be found at https://github.com/CSUBioGroup/DMFLDA2.