Knowledge Graph Convolutional Network with Heuristic Search for Drug Repositioning.

Drug repositioning is a strategy of repurposing approved drugs for treating new indications, which can accelerate the drug discovery process, reduce development costs, and lower the safety risk. The advancement of biotechnology has significantly accelerated the speed and scale of biological data generation, offering significant potential for drug repositioning through biomedical knowledge graphs that integrate diverse entities and relations from various biomedical sources. To fully learn the semantic information and topological structure information from the biological knowledge graph, we propose a knowledge graph convolutional network with a heuristic search, named KGCNH, which can effectively utilize the diversity of entities and relationships in biological knowledge graphs, as well as topological structure information, to predict the associations between drugs and diseases. Specifically, we design a relation-aware attention mechanism to compute the attention scores for each neighboring entity of a given entity under different relations. To address the challenge of randomness of the initial attention scores potentially impacting model performance and to expand the search scope of the model, we designed a heuristic search module based on Gumbel-Softmax, which uses attention scores as heuristic information and introduces randomness to assist the model in exploring more optimal embeddings of drugs and diseases. Following this module, we derive the relation weights, obtain the embeddings of drugs and diseases through neighborhood aggregation, and then predict drug-disease associations. Additionally, we employ feature-based augmented views to enhance model robustness and mitigate overfitting issues. We have implemented our method and conducted experiments on two data sets. The results demonstrate that KGCNH outperforms competing methods. In particular, case studies on lithium and quetiapine confirm that KGCNH can retrieve more actual drug-disease associations in the top prediction results.

DRGCL: Drug Repositioning via Semantic-enriched Graph Contrastive Learning.

Drug repositioning greatly reduces drug development costs and time by discovering new indications for existing drugs. With the development of technology and large-scale biological databases, computational drug repositioning has increasingly attracted remarkable attention, which can narrow down repositioning candidates. Recently, graph neural networks (GNNs) have been widely used and achieved promising results in drug repositioning. However, the existing GNNs based methods usually focus on modeling the complex drug-disease association graph, but ignore the semantic information on the graph, which may lead to a lack of consistency of global topology information and local semantic information for the learned features. To alleviate the above challenge, we propose a novel drug repositioning model based on graph contrastive learning, termed DRGCL. First, we treat the known drug-disease associations as the topology graph. Second, we select the top- K similar neighbor from drug/disease similarity information to construct the semantic graph rather than use the traditional data augmentation strategy, thereby maximally retaining rich semantic information. Finally, we pull closer to embedding consistency of the different embedding spaces by graph contrastive learning to enhance the topology and semantic feature on the graph. We have evaluated DRGCL on four benchmark datasets and the experiment results show that the proposed DRGCL is superior to the state-of-the-art methods. Especially, the average result of DRGCL is 11.92% higher than that of the second-best method in terms of AUPRC. The case studies further demonstrate the reliability of DRGCL. Experimental datasets and experimental codes can be found in https://github.com/Jiaxiao123/DRGCL.

Drug repositioning with adaptive graph convolutional networks.

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.

Partner-Specific Drug Repositioning Approach Based on Graph Convolutional Network.

Drug repositioning identifies novel therapeutic potentials for existing drugs and is considered an attractive approach due to the opportunity for reduced development timelines and overall costs. Prior computational methods usually learned a drug's representation from an entire graph of drug-disease associations. Therefore, the representation of learned drugs representation are static and agnostic to various diseases. However, for different diseases, a drug's mechanism of actions (MoAs) are different. The relevant context information should be differentiated for the same drug to target different diseases. Computational methods are thus required to learn different representations corresponding to different drug-disease associations for the given drug. In view of this, we propose an end-to-end partner-specific drug repositioning approach based on graph convolutional network, named PSGCN. PSGCN firstly extracts specific context information around drug-disease pairs from an entire graph of drug-disease associations. Then, it implements a graph convolutional network on the extracted graph to learn partner-specific graph representation. As the different layers of graph convolutional network contribute differently to the representation of the partner-specific graph, we design a layer self-attention mechanism to capture multi-scale layer information. Finally, PSGCN utilizes sortpool strategy to obtain the partner-specific graph embedding and formulates a drug-disease association prediction as a graph classification task. A fully-connected module is established to classify the partner-specific graph representations. The experiments on three benchmark datasets prove that the representation learning of partner-specific graph can lead to superior performances over state-of-the-art methods. In particular, case studies on small cell lung cancer and breast carcinoma confirmed that PSGCN is able to retrieve more actual drug-disease associations in the top prediction results. Moreover, in comparison with other static approaches, PSGCN can partly distinguish the different disease context information for the given drug.

The Warsaw breakage syndrome-related protein DDX11 is required for ribosomal RNA synthesis and embryonic development.

DDX11 was recently identified as a cause of Warsaw breakage syndrome (WABS). However, the functional mechanism of DDX11 and the contribution of clinically described mutations to the pathogenesis of WABS are elusive. Here, we show that DDX11 is a novel nucleolar protein that preferentially binds to hypomethylated active ribosomal DNA (rDNA) gene loci, where it interacts with upstream binding factor (UBF) and the RNA polymerase I (Pol I). DDX11 knockdown changed the epigenetic state of rDNA loci from euchromatic structures to more heterochromatic structures, reduced the activity of UBF, decreased the recruitment of UBF and RPA194 (a subunit of Pol I) to rDNA promoter, suppressed rRNA transcription and thereby inhibited growth and proliferation of HeLa cells. Importantly, two indentified WABS-derived mutants, R263Q and K897del, and a Fe-S deletion construct demonstrated significantly reduced binding abilities to rDNA promoters and lowered DNA-dependent ATPase activities compared with wild-type DDX11. Knockdown of the zebrafish ortholog of human DDX11 by morpholinos resulted in growth retardation and vertebral and craniofacial malformations in zebrafish, concomitant with the changes in histone epigenetic modifications at rDNA loci, the reduction of Pol I recruitment to the rDNA promoter and a significant decrease in nascent pre-RNA levels. These growth disruptions in zebrafish in response to DDX11 reduction showed similarities to the clinically described developmental abnormalities found in WABS patients for the first time in any vertebrate. Thus, our results indicate that DDX11 functions as a positive regulator of rRNA transcription and provides a novel insight into the pathogenesis of WABS.