DDAffinity: predicting the changes in binding affinity of multiple point mutations using protein 3D structure.

MOTIVATION: Mutations are the crucial driving force for biological evolution as they can disrupt protein stability and protein-protein interactions which have notable impacts on protein structure, function, and expression. However, existing computational methods for protein mutation effects prediction are generally limited to single point mutations with global dependencies, and do not systematically take into account the local and global synergistic epistasis inherent in multiple point mutations. RESULTS: To this end, we propose a novel spatial and sequential message passing neural network, named DDAffinity, to predict the changes in binding affinity caused by multiple point mutations based on protein 3D structures. Specifically, instead of being on the whole protein, we perform message passing on the k-nearest neighbor residue graphs to extract pocket features of the protein 3D structures. Furthermore, to learn global topological features, a two-step additive Gaussian noising strategy during training is applied to blur out local details of protein geometry. We evaluate DDAffinity on benchmark datasets and external validation datasets. Overall, the predictive performance of DDAffinity is significantly improved compared with state-of-the-art baselines on multiple point mutations, including end-to-end and pre-training based methods. The ablation studies indicate the reasonable design of all components of DDAffinity. In addition, applications in nonredundant blind testing, predicting mutation effects of SARS-CoV-2 RBD variants, and optimizing human antibody against SARS-CoV-2 illustrate the effectiveness of DDAffinity. AVAILABILITY AND IMPLEMENTATION: DDAffinity is available at https://github.com/ak422/DDAffinity.

DTKGIN: Predicting drug-target interactions based on knowledge graph and intent graph.

Knowledge graph intent graph attention mechanism Predicting drug-target interactions (DTIs) plays a crucial role in drug discovery and drug development. Considering the high cost and risk of biological experiments, developing computational approaches to explore the interactions between drugs and targets can effectively reduce the time and cost of drug development. Recently, many methods have made significant progress in predicting DTIs. However, existing approaches still suffer from the high sparsity of DTI datasets and the cold start problem. In this paper, we develop a new model to predict drug-target interactions via a knowledge graph and intent graph named DTKGIN. Our method can effectively capture biological environment information for targets and drugs by mining their associated relations in the knowledge graph and considering drug-target interactions at a fine-grained level in the intent graph. DTKGIN learns the representation of drugs and targets from the knowledge graph and the intent graph. Then the probabilities of interactions between drugs and targets are obtained through the inner product of the representation of drugs and targets. Experimental results show that our proposed method outperforms other state-of-the-art methods in 10-fold cross-validation, especially in cold-start experimental settings. Furthermore, the case studies demonstrate the effectiveness of DTKGIN in predicting potential drug-target interactions. The code is available on GitHub: https://github.com/Royluoyi123/DTKGIN.

A similarity-based deep learning approach for determining the frequencies of drug side effects.

The side effects of drugs present growing concern attention in the healthcare system. Accurately identifying the side effects of drugs is very important for drug development and risk assessment. Some computational models have been developed to predict the potential side effects of drugs and provided satisfactory performance. However, most existing methods can only predict whether side effects will occur and cannot determine the frequency of side effects. Although a few existing methods can predict the frequency of drug side effects, they strongly depend on the known drug-side effect relationships. Therefore, they cannot be applied to new drugs without known side effect frequency information. In this paper, we develop a novel similarity-based deep learning method, named SDPred, for determining the frequencies of drug side effects. Compared with the existing state-of-the-art models, SDPred integrates rich features and can be applied to predict the side effect frequencies of new drugs without any known drug-side effect association or frequency information. To our knowledge, this is the first work that can predict the side effect frequencies of new drugs in the population. The comparison results indicate that SDPred is much superior to all previously reported models. In addition, some case studies also demonstrate the effectiveness of our proposed method in practical applications. The SDPred software and data are freely available at https://github.com/zhc940702/SDPred, https://zenodo.org/record/5112573 and https://hub.docker.com/r/zhc940702/sdpred.

NASMDR: a framework for miRNA-drug resistance prediction using efficient neural architecture search and graph isomorphism networks.

As a frontier field of individualized therapy, microRNA (miRNA) pharmacogenomics facilitates the understanding of different individual responses to certain drugs and provides a reasonable reference for clinical treatment. However, the known drug resistance-associated miRNAs are not yet sufficient to support precision medicine. Although existing methods are effective, they all focus on modelling miRNA-drug resistance interaction graphs, making their performance bounded by the interaction density. In this study, we propose a framework for miRNA-drug resistance prediction through efficient neural architecture search and graph isomorphism networks (NASMDR). NASMDR uses attribute information instead of the commonly used interactive graph information. In the cross-validation experiment, the proposed framework can achieve an AUC of 0.9468 on the ncDR dataset, which is 2.29% higher than the state-of-the-art method. In addition, we propose a novel sequence characterization approach, k-mer Sparse Nonnegative Matrix Factorization (KSNMF). The results show that NASMDR provides novel insights for integrating efficient neural architecture search and graph isomorphic networks into a unified framework to predict drug resistance-related miRNAs. The codes for NASMDR are available at https://github.com/kaizheng-academic/NASMDR.

SSLpheno: a self-supervised learning approach for gene-phenotype association prediction using protein-protein interactions and gene ontology data.

MOTIVATION: Medical genomics faces significant challenges in interpreting disease phenotype and genetic heterogeneity. Despite the establishment of standardized disease phenotype databases, computational methods for predicting gene-phenotype associations still suffer from imbalanced category distribution and a lack of labeled data in small categories. RESULTS: To address the problem of labeled-data scarcity, we propose a self-supervised learning strategy for gene-phenotype association prediction, called SSLpheno. Our approach utilizes an attributed network that integrates protein-protein interactions and gene ontology data. We apply a Laplacian-based filter to ensure feature smoothness and use self-supervised training to optimize node feature representation. Specifically, we calculate the cosine similarity of feature vectors and select positive and negative sample nodes for reconstruction training labels. We employ a deep neural network for multi-label classification of phenotypes in the downstream task. Our experimental results demonstrate that SSLpheno outperforms state-of-the-art methods, especially in categories with fewer annotations. Moreover, our case studies illustrate the potential of SSLpheno as an effective prescreening tool for gene-phenotype association identification. AVAILABILITY AND IMPLEMENTATION: https://github.com/bixuehua/SSLpheno.

MSDRP: a deep learning model based on multisource data for predicting drug response.

MOTIVATION: Cancer heterogeneity drastically affects cancer therapeutic outcomes. Predicting drug response in vitro is expected to help formulate personalized therapy regimens. In recent years, several computational models based on machine learning and deep learning have been proposed to predict drug response in vitro. However, most of these methods capture drug features based on a single drug description (e.g. drug structure), without considering the relationships between drugs and biological entities (e.g. target, diseases, and side effects). Moreover, most of these methods collect features separately for drugs and cell lines but fail to consider the pairwise interactions between drugs and cell lines. RESULTS: In this paper, we propose a deep learning framework, named MSDRP for drug response prediction. MSDRP uses an interaction module to capture interactions between drugs and cell lines, and integrates multiple associations/interactions between drugs and biological entities through similarity network fusion algorithms, outperforming some state-of-the-art models in all performance measures for all experiments. The experimental results of de novo test and independent test demonstrate the excellent performance of our model for new drugs. Furthermore, several case studies illustrate the rationality for using feature vectors derived from drug similarity matrices from multisource data to represent drugs and the interpretability of our model. AVAILABILITY AND IMPLEMENTATION: The codes of MSDRP are available at https://github.com/xyzhang-10/MSDRP.

Computational drug repositioning based on multi-similarities bilinear matrix factorization.

With the development of high-throughput technology and the accumulation of biomedical data, the prior information of biological entity can be calculated from different aspects. Specifically, drug-drug similarities can be measured from target profiles, drug-drug interaction and side effects. Similarly, different methods and data sources to calculate disease ontology can result in multiple measures of pairwise disease similarities. Therefore, in computational drug repositioning, developing a dynamic method to optimize the fusion process of multiple similarities is a crucial and challenging task. In this study, we propose a multi-similarities bilinear matrix factorization (MSBMF) method to predict promising drug-associated indications for existing and novel drugs. Instead of fusing multiple similarities into a single similarity matrix, we concatenate these similarity matrices of drug and disease, respectively. Applying matrix factorization methods, we decompose the drug-disease association matrix into a drug-feature matrix and a disease-feature matrix. At the same time, using these feature matrices as basis, we extract effective latent features representing the drug and disease similarity matrices to infer missing drug-disease associations. Moreover, these two factored matrices are constrained by non-negative factorization to ensure that the completed drug-disease association matrix is biologically interpretable. In addition, we numerically solve the MSBMF model by an efficient alternating direction method of multipliers algorithm. The computational experiment results show that MSBMF obtains higher prediction accuracy than the state-of-the-art drug repositioning methods in cross-validation experiments. Case studies also demonstrate the effectiveness of our proposed method in practical applications. Availability: The data and code of MSBMF are freely available at https://github.com/BioinformaticsCSU/MSBMF. Corresponding author: Jianxin Wang, School of Computer Science and Engineering, Central South University, Changsha, Hunan 410083, P. R. China. E-mail: jxwang@mail.csu.edu.cn Supplementary Data: Supplementary data are available online at https://academic.oup.com/bib.

IIFDTI: predicting drug-target interactions through interactive and independent features based on attention mechanism.

MOTIVATION: Identifying drug-target interactions is a crucial step for drug discovery and design. Traditional biochemical experiments are credible to accurately validate drug-target interactions. However, they are also extremely laborious, time-consuming and expensive. With the collection of more validated biomedical data and the advancement of computing technology, the computational methods based on chemogenomics gradually attract more attention, which guide the experimental verifications. RESULTS: In this study, we propose an end-to-end deep learning-based method named IIFDTI to predict drug-target interactions (DTIs) based on independent features of drug-target pairs and interactive features of their substructures. First, the interactive features of substructures between drugs and targets are extracted by the bidirectional encoder-decoder architecture. The independent features of drugs and targets are extracted by the graph neural networks and convolutional neural networks, respectively. Then, all extracted features are fused and inputted into fully connected dense layers in downstream tasks for predicting DTIs. IIFDTI takes into account the independent features of drugs/targets and simulates the interactive features of the substructures from the biological perspective. Multiple experiments show that IIFDTI outperforms the state-of-the-art methods in terms of the area under the receiver operating characteristics curve (AUC), the area under the precision-recall curve (AUPR), precision, and recall on benchmark datasets. In addition, the mapped visualizations of attention weights indicate that IIFDTI has learned the biological knowledge insights, and two case studies illustrate the capabilities of IIFDTI in practical applications. AVAILABILITY AND IMPLEMENTATION: The data and codes underlying this article are available in Github at https://github.com/czjczj/IIFDTI. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

HyperAttentionDTI: improving drug-protein interaction prediction by sequence-based deep learning with attention mechanism.

MOTIVATION: Identifying drug-target interactions (DTIs) is a crucial step in drug repurposing and drug discovery. Accurately identifying DTIs in silico can significantly shorten development time and reduce costs. Recently, many sequence-based methods are proposed for DTI prediction and improve performance by introducing the attention mechanism. However, these methods only model single non-covalent inter-molecular interactions among drugs and proteins and ignore the complex interaction between atoms and amino acids. RESULTS: In this article, we propose an end-to-end bio-inspired model based on the convolutional neural network (CNN) and attention mechanism, named HyperAttentionDTI, for predicting DTIs. We use deep CNNs to learn the feature matrices of drugs and proteins. To model complex non-covalent inter-molecular interactions among atoms and amino acids, we utilize the attention mechanism on the feature matrices and assign an attention vector to each atom or amino acid. We evaluate HpyerAttentionDTI on three benchmark datasets and the results show that our model achieves significantly improved performance compared with the state-of-the-art baselines. Moreover, a case study on the human Gamma-aminobutyric acid receptors confirm that our model can be used as a powerful tool to predict DTIs. AVAILABILITY AND IMPLEMENTATION: The codes of our model are available at https://github.com/zhaoqichang/HpyerAttentionDTI and https://zenodo.org/record/5039589. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

DLP: Duplex Link Prediction Via Subspace Segmentation for Predicting drug-MiRNA Associations.

The arduous and costly journey of drug discovery is increasingly intersecting with computational approaches, which promise to accelerate the analysis of bioassays and biomedical literature. The critical role of microRNAs (miRNAs) in disease progression has been underscored in recent studies, elevating them as potential therapeutic targets. This emphasizes the need for the development of sophisticated computational models that can effectively identify promising drug targets, such as miRNAs. Herein, we present a novel method, termed Duplex Link Prediction (DLP), rooted in subspace segmentation, to pinpoint potential miRNA targets. Our approach initiates with the application of the Network Enhancement (NE) algorithm to refine the similarity metric between miRNAs. Thereafter, we construct two matrices by pre-loading the association matrix from both the drug and miRNA perspectives, employing the K Nearest Neighbors (KNN) technique. The DLSR algorithm is then applied to predict potential associations. The final predicted association scores are ascertained through the weighted mean of the two matrices. Our empirical findings suggest that the DLP algorithm outperforms current methodologies in the realm of identifying potential miRNA drug targets. Case study validations further reinforce the real-world applicability and effectiveness of our proposed method. The code of DLP is freely available at https://github.com/kaizheng-academic/DLP.

RGCNPPIS: A Residual Graph Convolutional Network for Protein-Protein Interaction Site Prediction.

Accurate identification of protein-protein interaction (PPI) sites is crucial for understanding the mechanisms of biological processes, developing PPI networks, and detecting protein functions. Currently, most computational methods primarily concentrate on sequence context features and rarely consider the spatial neighborhood features. To address this limitation, we propose a novel residual graph convolutional network for structure-based PPI site prediction (RGCNPPIS). Specifically, we use a GCN module to extract the global structural features from all spatial neighborhoods, and utilize the GraphSage module to extract local structural features from local spatial neighborhoods. To the best of our knowledge, this is the first work utilizing local structural features for PPI site prediction. We also propose an enhanced residual graph connection to combine the initial node representation, local structural features, and the previous GCN layer's node representation, which enables information transfer between layers and alleviates the over-smoothing problem. Evaluation results demonstrate that RGCNPPIS outperforms state-of-the-art methods on three independent test sets. In addition, the results of ablation experiments and case studies confirm that RGCNPPIS is an effective tool for PPI site prediction.

AttentionDTA: Drug-Target Binding Affinity Prediction by Sequence-Based Deep Learning With Attention Mechanism.

The identification of drug-target relations (DTRs) is substantial in drug development. A large number of methods treat DTRs as drug-target interactions (DTIs), a binary classification problem. The main drawback of these methods are the lack of reliable negative samples and the absence of many important aspects of DTR, including their dose dependence and quantitative affinities. With increasing number of publications of drug-protein binding affinity data recently, DTRs prediction can be viewed as a regression problem of drug-target affinities (DTAs) which reflects how tightly the drug binds to the target and can present more detailed and specific information than DTIs. The growth of affinity data enables the use of deep learning architectures, which have been shown to be among the state-of-the-art methods in binding affinity prediction. Although relatively effective, due to the black-box nature of deep learning, these models are less biologically interpretable. In this study, we proposed a deep learning-based model, named AttentionDTA, which uses attention mechanism to predict DTAs. Different from the models using 3D structures of drug-target complexes or graph representation of drugs and proteins, the novelty of our work is to use attention mechanism to focus on key subsequences which are important in drug and protein sequences when predicting its affinity. We use two separate one-dimensional Convolution Neural Networks (1D-CNNs) to extract the semantic information of drug's SMILES string and protein's amino acid sequence. Furthermore, a two-side multi-head attention mechanism is developed and embedded to our model to explore the relationship between drug features and protein features. We evaluate our model on three established DTA benchmark datasets, Davis, Metz, and KIBA. AttentionDTA outperforms the state-of-the-art deep learning methods under different evaluation metrics. The results show that the attention-based model can effectively extract protein features related to drug information and drug features related to protein information to better predict drug target affinities. It is worth mentioning that we test our model on IC50 dataset, which provides the binding sites between drugs and proteins, to evaluate the ability of our model to locate binding sites. Finally, we visualize the attention weight to demonstrate the biological significance of the model. The source code of AttentionDTA can be downloaded from https://github.com/zhaoqichang/AttentionDTA_TCBB.

GIFDTI: Prediction of Drug-Target Interactions Based on Global Molecular and Intermolecular Interaction Representation Learning.

Drug discovery and drug repurposing often rely on the successful prediction of drug-target interactions (DTIs). Recent advances have shown great promise in applying deep learning to drug-target interaction prediction. One challenge in building deep learning-based models is to adequately represent drugs and proteins that encompass the fundamental local chemical environments and long-distance information among amino acids of proteins (or atoms of drugs). Another challenge is to efficiently model the intermolecular interactions between drugs and proteins, which plays vital roles in the DTIs. To this end, we propose a novel model, GIFDTI, which consists of three key components: the sequence feature extractor (CNNFormer), the global molecular feature extractor (GF), and the intermolecular interaction modeling module (IIF). Specifically, CNNFormer incorporates CNN and Transformer to capture the local patterns and encode the long-distance relationship among tokens (atoms or amino acids) in a sequence. Then, GF and IIF extract the global molecular features and the intermolecular interaction features, respectively. We evaluate GIFDTI on six realistic evaluation strategies and the results show it improves DTI prediction performance compared to state-of-the-art methods. Moreover, case studies confirm that our model can be a useful tool to accurately yield low-cost DTIs. The codes of GIFDTI are available at https://github.com/zhaoqichang/GIFDTI.

Identifying the serious clinical outcomes of adverse reactions to drugs by a multi-task deep learning framework.

Adverse Drug Reactions (ADRs) have a direct impact on human health. As continuous pharmacovigilance and drug monitoring prove to be costly and time-consuming, computational methods have emerged as promising alternatives. However, most existing computational methods primarily focus on predicting whether or not the drug is associated with an adverse reaction and do not consider the core issue of drug benefit-risk assessment-whether the treatment outcome is serious when adverse drug reactions occur. To this end, we categorize serious clinical outcomes caused by adverse reactions to drugs into seven distinct classes and present a deep learning framework, so-called GCAP, for predicting the seriousness of clinical outcomes of adverse reactions to drugs. GCAP has two tasks: one is to predict whether adverse reactions to drugs cause serious clinical outcomes, and the other is to infer the corresponding classes of serious clinical outcomes. Experimental results demonstrate that our method is a powerful and robust framework with high extendibility. GCAP can serve as a useful tool to successfully address the challenge of predicting the seriousness of clinical outcomes stemming from adverse reactions to drugs.

Biomedical Data and Deep Learning Computational Models for Predicting Compound-Protein Relations.

The identification of compound-protein relations (CPRs), which includes compound-protein interactions (CPIs) and compound-protein affinities (CPAs), is critical to drug development. A common method for compound-protein relation identification is the use of in vitro screening experiments. However, the number of compounds and proteins is massive, and in vitro screening experiments are labor-intensive, expensive, and time-consuming with high failure rates. Researchers have developed a computational field called virtual screening (VS) to aid experimental drug development. These methods utilize experimentally validated biological interaction information to generate datasets and use the physicochemical and structural properties of compounds and target proteins as input information to train computational prediction models. At present, deep learning has been widely used in computer vision and natural language processing and has experienced epoch-making progress. At the same time, deep learning has also been used in the field of biomedicine widely, and the prediction of CPRs based on deep learning has developed rapidly and has achieved good results. The purpose of this study is to investigate and discuss the latest applications of deep learning techniques in CPR prediction. First, we describe the datasets and feature engineering (i.e., compound and protein representations and descriptors) commonly used in CPR prediction methods. Then, we review and classify recent deep learning approaches in CPR prediction. Next, a comprehensive comparison is performed to demonstrate the prediction performance of representative methods on classical datasets. Finally, we discuss the current state of the field, including the existing challenges and our proposed future directions. We believe that this investigation will provide sufficient references and insight for researchers to understand and develop new deep learning methods to enhance CPR predictions.