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Motivation The emergence of drug-resistant bacteria makes the discovery of new antibiotics an urgent issue, but finding new molecules with the desired antibacterial activity is an extremely difficult task. To address this challenge, we established a framework, MDAGS (Molecular Design via Attribute-Guided Search), to optimize and generate potent antibiotic molecules. Results By designing the antibacterial activity latent space and guiding the optimization of functional compounds based on this space, the model MDAGS can generate novel compounds with desirable antibacterial activity without the need for extensive expensive and time-consuming evaluations. Compared with existing antibiotics, candidate antibacterial compounds generated by MDAGS always possessed significantly better antibacterial activity and ensured high similarity. Furthermore, although without explicit constraints on similarity to known antibiotics, these candidate antibacterial compounds all exhibited the highest structural similarity to antibiotics of expected function in the DrugBank database query. Overall, our approach provides a viable solution to the problem of bacterial drug resistance. Availability and implementation Code of the model and datasets can be downloaded from GitHub (https://github.com/LiangYu-Xidian/MDAGS). Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Motivation Approaches for the diagnosis and treatment of diseases often adopt the multidrug therapy method because it can increase the efficacy or reduce the toxic side effects of drugs. Using different drugs simultaneously may trigger unexpected pharmacological effects. Therefore, efficient identification of drug interactions is essential for the treatment of complex diseases. Currently proposed calculation methods are often limited by the collection of redundant drug features, a small amount of labeled data and low model generalization capabilities. Meanwhile, there is also a lack of unique methods for multidrug representation learning, which makes it more difficult to take full advantage of the originally scarce data. Results Inspired by graph models and pretraining models, we integrated a large amount of unlabeled drug molecular graph information and target information, then designed a pretraining framework, MGP-DR (Molecular Graph Pretraining for Drug Representation), specifically for drug pair representation learning. The model uses self-supervised learning strategies to mine the contextual information within and between drug molecules to predict drug–drug interactions and drug combinations. The results achieved promising performance across multiple metrics compared with other state-of-the-art methods. Our MGP-DR model can be used to provide a reliable candidate set for the combined use of multiple drugs. Availability and implementation Code of the model, datasets and results can be downloaded from GitHub (https://github.com/LiangYu-Xidian/MGP-DR). Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

With an in-depth understanding of noncoding ribonucleic acid (RNA), many studies have shown that microRNA (miRNA) plays an important role in human diseases. Because traditional biological experiments are time-consuming and laborious, new calculation methods have recently been developed to predict associations between miRNA and diseases. In this review, we collected various miRNA–disease association prediction models proposed in recent years and used two common data sets to evaluate the performance of the prediction models. First, we systematically summarized the commonly used databases and similarity data for predicting miRNA–disease associations, and then divided the various calculation models into four categories for summary and detailed introduction. In this study, two independent datasets (D 5430 and D 6088) were compiled to systematically evaluate 11 publicly available prediction tools for miRNA–disease associations. The experimental results indicate that the methods based on information dissemination and the method based on scoring function require shorter running time. The method based on matrix transformation often requires a longer running time, but the overall prediction result is better than the previous two methods. We hope that the summary of work related to miRNA and disease will provide comprehensive knowledge for predicting the relationship between miRNA and disease and contribute to advanced computation tools in the future. [ABSTRACT FROM AUTHOR]

Since miRNAs can participate in the posttranscriptional regulation of gene expression, they may provide ideas for the development of new drugs or become new biomarkers for drug targets or disease diagnosis. In this work, we propose an miRNA–disease association prediction method based on meta-paths (MDPBMP). First, an miRNA–disease–gene heterogeneous information network was constructed, and seven symmetrical meta-paths were defined according to different semantics. After constructing the initial feature vector for the node, the vector information carried by all nodes on the meta-path instance is extracted and aggregated to update the feature vector of the starting node. Then, the vector information obtained by the nodes on different meta-paths is aggregated. Finally, miRNA and disease embedding feature vectors are used to calculate their associated scores. Compared with the other methods, MDPBMP obtained the highest AUC value of 0.9214. Among the top 50 predicted miRNAs for lung neoplasms, esophageal neoplasms, colon neoplasms and breast neoplasms, 49, 48, 49 and 50 have been verified. Furthermore, for breast neoplasms, we deleted all the known associations between breast neoplasms and miRNAs from the training set. These results also show that for new diseases without known related miRNA information, our model can predict their potential miRNAs. Code and data are available at https://github.com/LiangYu-Xidian/MDPBMP. [ABSTRACT FROM AUTHOR]

Drug combination is a sensible strategy for disease treatment because it improves the treatment efficacy and reduces concomitant side effects. Due to the large number of possible combinations among candidate compounds, exhaustive screening is prohibitive. Currently, a large number of studies have focused on predicting potential drug combinations. However, these methods are not entirely satisfactory in terms of performance and scalability. In this paper, we proposed a Network Embedding frameWork in MultIplex Network (NEWMIN) to predict synthetic drug combinations. Based on a multiplex drug similarity network, we offered alternative methods to integrate useful information from different aspects and to decide the quantitative importance of each network. For drug combination prediction, we found seven novel drug combinations that have been validated by external sources among the top-ranked predictions of our model. To verify the feasibility of NEWMIN, we compared NEWMIN with other five methods, for which it showed better performance than other methods in terms of the area under the precision-recall curve and receiver operating characteristic curve. [ABSTRACT FROM AUTHOR]

Motivation The heterologous expression of recombinant protein requires host cells, such as Escherichiacoli , and the solubility of protein greatly affects the protein yield. A novel and highly accurate solubility predictor that concurrently improves the production yield and minimizes production cost, and that forecasts protein solubility in an E.coli expression system before the actual experimental work is highly sought. Results In this article, EPSOL, a novel deep learning architecture for the prediction of protein solubility in an E.coli expression system, which automatically obtains comprehensive protein feature representations using multidimensional embedding, is presented. EPSOL outperformed all existing sequence-based solubility predictors and achieved 0.79 in accuracy and 0.58 in Matthew's correlation coefficient. The higher performance of EPSOL permits large-scale screening for sequence variants with enhanced manufacturability and predicts the solubility of new recombinant proteins in an E.coli expression system with greater reliability. Availability and implementation EPSOL's best model and results can be downloaded from GitHub (https://github.com/LiangYu-Xidian/EPSOL). Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Accurate prediction of drug-target interactions (DTIs) through biological data can reduce the time and economic cost of drug development. The prediction method of DTIs based on a similarity network is attracting increasing attention. Currently, many studies have focused on predicting DTIs. However, such approaches do not consider the features of drugs and targets in multiple networks or how to extract and merge them. In this study, we proposed a Network EmbeDding framework in mulTiPlex networks (NEDTP) to predict DTIs. NEDTP builds a similarity network of nodes based on 15 heterogeneous information networks. Next, we applied a random walk to extract the topology information of each node in the network and learn it as a low-dimensional vector. Finally, the Gradient Boosting Decision Tree model was constructed to complete the classification task. NEDTP achieved accurate results in DTI prediction, showing clear advantages over several state-of-the-art algorithms. The prediction of new DTIs was also verified from multiple perspectives. In addition, this study also proposes a reasonable model for the widespread negative sampling problem of DTI prediction, contributing new ideas to future research. Code and data are available at https://github.com/LiangYu-Xidian/NEDTP. [ABSTRACT FROM AUTHOR]

Protein–nucleic acid interactions play essential roles in many biological processes, such as transcription, replication and translation. In protein–nucleic acid interfaces, hotspot residues contribute the majority of binding affinity toward molecular recognition. Hotspot residues are commonly regarded as potential binding sites for compound molecules in drug design projects. The dynamic property is a considerable factor that affects the binding of ligands. Computational approaches have been developed to expedite the prediction of hotspot residues on protein–nucleic acid interfaces. However, existing approaches overlook hotspot dynamics, despite their essential role in protein function. Here, we report a web server named Hotspots In silico Scanning on Nucleic Acid and Protein Interface (HISNAPI) to analyze hotspot residue dynamics by integrating molecular dynamics simulation and one-step free energy perturbation. HISNAPI is capable of not only predicting the hotspot residues in protein–nucleic acid interfaces but also providing insights into their intensity and correlation of dynamic motion. Protein dynamics have been recognized as a vital factor that has an effect on the interaction specificity and affinity of the binding partners. We applied HISNAPI to the case of SARS-CoV-2 RNA-dependent RNA polymerase, a vital target of the antiviral drug for the treatment of coronavirus disease 2019. We identified the hotspot residues and characterized their dynamic behaviors, which might provide insight into the target site for antiviral drug design. The web server is freely available via a user-friendly web interface at http://chemyang.ccnu.edu.cn/ccb/server/HISNAPI/ and http://agroda.gzu.edu.cn:9999/ccb/server/HISNAPI/. [ABSTRACT FROM AUTHOR]

Effective drug discovery contributes to the treatment of numerous diseases but is limited by high costs and long cycles. The Quantitative Structure–Activity Relationship (QSAR) method was introduced to evaluate the activity of a large number of compounds virtually, reducing the time and labor costs required for chemical synthesis and experimental determination. Hence, this method increases the efficiency of drug discovery. To meet the needs of researchers to utilize this technology, numerous QSAR-related web servers, such as Web-4D-QSAR and DPubChem, have been developed in recent years. However, none of the servers mentioned above can perform a complete QSAR modeling and supply activity prediction functions. We introduce Cloud 3D-QSAR by integrating the functions of molecular structure generation, alignment, molecular interaction field (MIF) computing and results analysis to provide a one-stop solution. We rigidly validated this server, and the activity prediction correlation was R 2 = 0.934 in 834 test molecules. The sensitivity, specificity and accuracy were 86.9%, 94.5% and 91.5%, respectively, with AUC = 0.981, AUCPR = 0.971. The Cloud 3D-QSAR server may facilitate the development of good QSAR models in drug discovery. Our server is free and now available at http://chemyang.ccnu.edu.cn/ccb/server/cloud3dQSAR/ and http://agroda.gzu.edu.cn:9999/ccb/server/cloud3dQSAR/. [ABSTRACT FROM AUTHOR]

Arteriovenous malformations (AVMs) are fast-flow vascular malformations and refer to important causes of intracerebral haemorrhage in young adults. Getting deep insight into the genetic pathogenesis of AVMs is necessary. Herein, we identified two vital missense variants of G protein-coupled receptor (GPCR) associated sorting protein 1 (GPRASP1) in AVM patients for the first time and congruously determined to be loss-of-function variants in endothelial cells. GPRASP1 loss-of-function caused endothelial dysfunction in vitro and in vivo. Endothelial Gprasp1 knockout mice suffered a high probability of cerebral haemorrhage, AVMs and exhibited vascular anomalies in multiple organs. GPR4 was identified to be an effective GPCR binding with GPRASP1 to develop endothelial disorders. GPRASP1 deletion activated GPR4/cAMP/MAPK signalling to disturb endothelial functions, thus contributing to vascular anomalies. Mechanistically, GPRASP1 promoted GPR4 degradation. GPRASP1 enabled GPR4 K63-linked ubiquitination, enhancing the binding of GPR4 and RABGEF1 to activate RAB5 for conversions from endocytic vesicles to endosomes, and subsequently increasing the interactions of GPR4 and ESCRT members to package GPR4 into multivesicular bodies or late endosomes for lysosome degradation. Notably, the GPR4 antagonist NE 52-QQ57 and JNK inhibitor SP600125 effectively rescued the vascular phenotype caused by endothelial Gprasp1 deletion. Our findings provided novel insights into the roles of GPRASP1 in AVMs and hinted at new therapeutic strategies. [ABSTRACT FROM AUTHOR]

2'-O-methylation (Nm) is a post-transcriptional modification of RNA that is catalyzed by 2'-O-methyltransferase and involves replacing the H on the 2′-hydroxyl group with a methyl group. The 2'-O-methylation modification site is detected in a variety of RNA types (miRNA, tRNA, mRNA, etc.), plays an important role in biological processes and is associated with different diseases. There are few functional mechanisms developed at present, and traditional high-throughput experiments are time-consuming and expensive to explore functional mechanisms. For a deeper understanding of relevant biological mechanisms, it is necessary to develop efficient and accurate recognition tools based on machine learning. Based on this, we constructed a predictor called NmRF based on optimal mixed features and random forest classifier to identify 2'-O-methylation modification sites. The predictor can identify modification sites of multiple species at the same time. To obtain a better prediction model, a two-step strategy is adopted; that is, the optimal hybrid feature set is obtained by combining the light gradient boosting algorithm and incremental feature selection strategy. In 10-fold cross-validation, the accuracies of Homo sapiens and Saccharomyces cerevisiae were 89.069 and 93.885%, and the AUC were 0.9498 and 0.9832, respectively. The rigorous 10-fold cross-validation and independent tests confirm that the proposed method is significantly better than existing tools. A user-friendly web server is accessible at http://lab.malab.cn/∼acy/NmRF. [ABSTRACT FROM AUTHOR]

Protein post-translational modifications (PTM) play vital roles in cellular regulation, modulating functions by driving changes in protein structure and dynamics. Exploring comprehensively the influence of PTM on conformational dynamics can facilitate the understanding of the related biological function and molecular mechanism. Currently, a series of excellent computation tools have been designed to analyze the time-dependent structural properties of proteins. However, the protocol aimed to explore conformational dynamics of post-translational modified protein is still a blank. To fill this gap, we present PTMdyna to visually predict the conformational dynamics differences between unmodified and modified proteins, thus indicating the influence of specific PTM. PTMdyna exhibits an AUC of 0.884 tested on 220 protein–protein complex structures. The case of heterochromatin protein 1α complexed with lysine 9-methylated histone H3, which is critical for genomic stability and cell differentiation, was used to demonstrate its applicability. PTMdyna provides a reliable platform to predict the influence of PTM on protein dynamics, making it easier to interpret PTM functionality at the structure level. The web server is freely available at http://ccbportal.com/PTMdyna. [ABSTRACT FROM AUTHOR]

Glandular secretory trichomes (GSTs) can secrete and store a variety of specific metabolites. By increasing GST density, valuable metabolites can be enhanced in terms of productivity. However, the comprehensive and detailed regulatory network of GST initiation still needs further investigation. By screening a complementary DNA library derived from young leaves of Artemisia annua, we identified a MADS-box transcription factor, AaSEPALLATA1 (AaSEP1), that positively regulates GST initiation. Overexpression of AaSEP1 in A. annua substantially increased GST density and artemisinin content. The HOMEODOMAIN PROTEIN 1 (AaHD1)-AaMYB16 regulatory network regulates GST initiation via the jasmonate (JA) signaling pathway. In this study, AaSEP1 enhanced the function of AaHD1 activation on downstream GST initiation gene GLANDULAR TRICHOMESPECIFIC WRKY 2 (AaGSW2) through interaction with AaMYB16. Moreover, AaSEP1 interacted with the JA ZIM-domain 8 (AaJAZ8) and served as an important factor in JA-mediated GST initiation. We also found that AaSEP1 interacted with CONSTITUTIVE PHOTOMORPHOGENIC 1 (AaCOP1), a major repressor of light signaling. In this study, we identified a MADS-box transcription factor that is induced by JA and light signaling and that promotes the initiation of GST in A. annua. [ABSTRACT FROM AUTHOR]

Motivation Multiple sequence alignment (MSA) is a fundamental problem in bioinformatics. The quality of alignment will affect downstream analysis. MAFFT has adopted the Fast Fourier Transform method for searching the homologous segments and using them as anchors to divide the sequences, then making alignment only on segments, which can save time and memory without overly reducing the sequence alignment quality. MAFFT becomes slow when the dataset is large. Results We made a software, WMSA, which uses the divide-and-conquer method to split the sequences into clusters, aligns those clusters into profiles with the center star strategy and then makes a progressive profile–profile alignment. The alignment is conducted by the compiled algorithms of MAFFT, K-Band with multithread parallelism. Our method can balance time, space and quality and performs better than MAFFT in test experiments on highly conserved datasets. Availability and implementation Source code is freely available at https://github.com/malabz/WMSA/ , which is implemented in C/C++ and supported on Linux, and datasets are available at https://github.com/malabz/WMSA-dataset. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Accurate prediction of drug-target interactions (DTIs) can reduce the cost and time of drug repositioning and drug discovery. Many current methods integrate information from multiple data sources of drug and target to improve DTIs prediction accuracy. However, these methods do not consider the complex relationship between different data sources. In this study, we propose a novel computational framework, called MccDTI, to predict the potential DTIs by multiview network embedding, which can integrate the heterogenous information of drug and target. MccDTI learns high-quality low-dimensional representations of drug and target by preserving the consistent and complementary information between multiview networks. Then MccDTI adopts matrix completion scheme for DTIs prediction based on drug and target representations. Experimental results on two datasets show that the prediction accuracy of MccDTI outperforms four state-of-the-art methods for DTIs prediction. Moreover, literature verification for DTIs prediction shows that MccDTI can predict the reliable potential DTIs. These results indicate that MccDTI can provide a powerful tool to predict new DTIs and accelerate drug discovery. The code and data are available at: https://github.com/ShangCS/MccDTI. [ABSTRACT FROM AUTHOR]