Research Progresses and Applications of Knowledge Graph Embedding Technique in Chemistry.

A knowledge graph (KG) is a technique for modeling entities and their interrelations. Knowledge graph embedding (KGE) translates these entities and relationships into a continuous vector space to facilitate dense and efficient representations. In the domain of chemistry, applying KG and KGE techniques integrates heterogeneous chemical information into a coherent and user-friendly framework, enhances the representation of chemical data features, and is beneficial for downstream tasks, such as chemical property prediction. This paper begins with a comprehensive review of classical and contemporary KGE methodologies, including distance-based models, semantic matching models, and neural network-based approaches. We then catalogue the primary databases employed in chemistry and biochemistry that furnish the KGs with essential chemical data. Subsequently, we explore the latest applications of KG and KGE in chemistry, focusing on risk assessment, property prediction, and drug discovery. Finally, we discuss the current challenges to KG and KGE techniques and provide a perspective on their potential future developments.

Protein-Protein Interaction Site Prediction Based on Attention Mechanism and Convolutional Neural Networks.

Proteins usually perform their cellular functions by interacting with other proteins. Accurate identification of protein-protein interaction sites (PPIs) from sequence is import for designing new drugs and developing novel therapeutics. A lot of computational models for PPIs prediction have been developed because experimental methods are slow and expensive. Most models employ a sliding window approach in which local neighbors are concatenated to present a target residue. However, those neighbors are not distinguished by pairwise information between a neighbor and the target. In this study, we propose a novel PPIs prediction model AttCNNPPISP, which combines attention mechanism and convolutional neural networks (CNNs). The attention mechanism dynamically captures the pairwise correlation of each neighbor-target pair within a sliding window, and therefore makes a better understanding of the local environment of target residue. And then, CNNs take the local representation as input to make prediction. Experiments are employed on several public benchmark datasets. Compared with the state-of-the-art models, AttCNNPPISP improves the prediction performance. Also, the experimental results demonstrate that the attention mechanism is effective in terms of constructing comprehensive context information of target residue.

A Structure-Based B-cell Epitope Prediction Model Through Combing Local and Global Features.

B-cell epitopes (BCEs) are a set of specific sites on the surface of an antigen that binds to an antibody produced by B-cell. The recognition of BCEs is a major challenge for drug design and vaccines development. Compared with experimental methods, computational approaches have strong potential for BCEs prediction at much lower cost. Moreover, most of the currently methods focus on using local information around target residue without taking the global information of the whole antigen sequence into consideration. We propose a novel deep leaning method through combing local features and global features for BCEs prediction. In our model, two parallel modules are built to extract local and global features from the antigen separately. For local features, we use Graph Convolutional Networks (GCNs) to capture information of spatial neighbors of a target residue. For global features, Attention-Based Bidirectional Long Short-Term Memory (Att-BLSTM) networks are applied to extract information from the whole antigen sequence. Then the local and global features are combined to predict BCEs. The experiments show that the proposed method achieves superior performance over the state-of-the-art BCEs prediction methods on benchmark datasets. Also, we compare the performance differences between data with or without global features. The experimental results show that global features play an important role in BCEs prediction. Our detailed case study on the BCEs prediction for SARS-Cov-2 receptor binding domain confirms that our method is effective for predicting and clustering true BCEs.

Leveraging Sequential and Spatial Neighbors Information by Using CNNs Linked With GCNs for Paratope Prediction.

Antibodies consisting of variable and constant regions, are a special type of proteins playing a vital role in immune system of the vertebrate. They have the remarkable ability to bind a large range of diverse antigens with extraordinary affinity and specificity. This malleability of binding makes antibodies an important class of biological drugs and biomarkers. In this article, we propose a method to identify which amino acid residues of an antibody directly interact with its associated antigen based on the features from sequence and structure. Our algorithm uses convolution neural networks (CNNs) linked with graph convolution networks (GCNs) to make use of information from both sequential and spatial neighbors to understand more about the local environment of target amino acid residue. Furthermore, we process the antigen partner of an antibody by employing an attention layer. Our method improves on the state-of-the-art methodology.

Pitavastatin treatment induces neuroprotection through the BDNF-TrkB signalling pathway in cultured cerebral neurons after oxygen-glucose deprivation.

OBJECTIVES: Along with their lipid-lowering effect, statins have been reported to have neuroprotective function in both in vivo and in vitro models of neurodegenerative diseases. We conducted this study in order to uncover the he neuroprotective effect of the lipophilic statin pitavastatin (PTV) and investigate the underlying molecular mechanisms using primary cultured cerebral neurons exposed to oxygen-glucose deprivation (OGD). METHODS: The primary cultured cerebral neurons were randomly assigned into four groups: the control group, the pitavastatin treatment group, the OGD group and the OGD + pitavastatin treatment group. The pitavastatin's concentration were set as follows: 1µM, 15µM, 30µM. After 3 hours OGD treatment, we use MTT method to assessment cell viability, immunofluorescence to observe neuron morphology and western blot method analysis the BDNF, TrkB. RESULTS: PTV at concentrations of 1 µM and 15 µM elevated the survival rate of cortical neurons exposed to OGD, whereas 30 µM PTV did not show such an effect. Moreover, PTV promoted neuronal dendrite growth at concentrations of 1 µM and 15 µM. Increased expression levels of brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) were observed in both of the following two scenarios: when neurons were treated with PTV for 48 hours and when PTV was added after the OGD procedure. CONCLUSION: Pitavastatin treatment induces neuroprotection in cultured cerebral neurons after oxygen-glucose deprivation this neuroprotection induced by PTV involves the BDNF-TrkB signalling pathway.

Predicting chemical bioavailability using microarray gene expression data and regression modeling: A tale of three explosive compounds.

BACKGROUND: Chemical bioavailability is an important dose metric in environmental risk assessment. Although many approaches have been used to evaluate bioavailability, not a single approach is free from limitations. Previously, we developed a new genomics-based approach that integrated microarray technology and regression modeling for predicting bioavailability (tissue residue) of explosives compounds in exposed earthworms. In the present study, we further compared 18 different regression models and performed variable selection simultaneously with parameter estimation. RESULTS: This refined approach was applied to both previously collected and newly acquired earthworm microarray gene expression datasets for three explosive compounds. Our results demonstrate that a prediction accuracy of R(2) = 0.71-0.82 was achievable at a relatively low model complexity with as few as 3-10 predictor genes per model. These results are much more encouraging than our previous ones. CONCLUSION: This study has demonstrated that our approach is promising for bioavailability measurement, which warrants further studies of mixed contamination scenarios in field settings.

Quantitative Structure-Activity Relationship Analysis and a Combined Ligand-Based/Structure-Based Virtual Screening Study for Glycogen Synthase Kinase-3.

Glycogen synthase kinase-3 (GSK-3) is a multifunctional serine/threonine protein kinase which regulates a wide range of cellular processes, involving various signalling pathways. GSK-3ß has emerged as an important therapeutic target for diabetes and Alzheimer's disease. To identify structurally novel GSK-3ß inhibitors, we performed virtual screening by implementing a combined ligand-based/structure-based approach, which included quantitative structure-activity relationship (QSAR) analysis and docking prediction. To integrate and analyze complex data sets from multiple experimental sources, we drafted and validated a hierarchical QSAR method, which adopts a two-level structure to take data heterogeneity into account. A collection of 728 GSK-3 inhibitors with diverse structural scaffolds was obtained from published papers that used different experimental assay protocols. Support vector machines and random forests were implemented with wrapper-based feature selection algorithms to construct predictive learning models. The best models for each single group of compounds were then used to build the final hierarchical QSAR model, with an overall R(2) of 0.752 for the 141 compounds in the test set. The compounds obtained from the virtual screening experiment were tested for GSK-3ß inhibition. The bioassay results confirmed that 2 hit compounds are indeed GSK-3ß inhibitors exhibiting sub-micromolar inhibitory activity, and therefore validated our combined ligand-based/structure-based approach as effective for virtual screening experiments.

Implementation of multiple-instance learning in drug activity prediction.

BACKGROUND: In the context of drug discovery and development, much effort has been exerted to determine which conformers of a given molecule are responsible for the observed biological activity. In this work we aimed to predict bioactive conformers using a variant of supervised learning, named multiple-instance learning. A single molecule, treated as a bag of conformers, is biologically active if and only if at least one of its conformers, treated as an instance, is responsible for the observed bioactivity; and a molecule is inactive if none of its conformers is responsible for the observed bioactivity. The implementation requires instance-based embedding, and joint feature selection and classification. The goal of the present project is to implement multiple-instance learning in drug activity prediction, and subsequently to identify the bioactive conformers for each molecule. METHODS: We encoded the 3-dimensional structures using pharmacophore fingerprints which are binary strings, and accomplished instance-based embedding using calculated dissimilarity distances. Four dissimilarity measures were employed and their performances were compared. 1-norm SVM was used for joint feature selection and classification. The approach was applied to four data sets, and the best proposed model for each data set was determined by using the dissimilarity measure yielding the smallest number of selected features. RESULTS: The predictive abilities of the proposed approach were compared with three classical predictive models without instance-based embedding. The proposed approach produced the best predictive models for one data set and second best predictive models for the rest of the data sets, based on the external validations. To validate the ability of the proposed approach to find bioactive conformers, 12 small molecules with co-crystallized structures were seeded in one data set. 10 out of 12 co-crystallized structures were indeed identified as significant conformers using the proposed approach. CONCLUSIONS: The proposed approach was proven not to suffer from overfitting and to be highly competitive with classical predictive models, so it is very powerful for drug activity prediction. The approach was also validated as a useful method for pursuit of bioactive conformers.

Leveraging domain information to restructure biological prediction.

BACKGROUND: It is commonly believed that including domain knowledge in a prediction model is desirable. However, representing and incorporating domain information in the learning process is, in general, a challenging problem. In this research, we consider domain information encoded by discrete or categorical attributes. A discrete or categorical attribute provides a natural partition of the problem domain, and hence divides the original problem into several non-overlapping sub-problems. In this sense, the domain information is useful if the partition simplifies the learning task. The goal of this research is to develop an algorithm to identify discrete or categorical attributes that maximally simplify the learning task. RESULTS: We consider restructuring a supervised learning problem via a partition of the problem space using a discrete or categorical attribute. A naive approach exhaustively searches all the possible restructured problems. It is computationally prohibitive when the number of discrete or categorical attributes is large. We propose a metric to rank attributes according to their potential to reduce the uncertainty of a classification task. It is quantified as a conditional entropy achieved using a set of optimal classifiers, each of which is built for a sub-problem defined by the attribute under consideration. To avoid high computational cost, we approximate the solution by the expected minimum conditional entropy with respect to random projections. This approach is tested on three artificial data sets, three cheminformatics data sets, and two leukemia gene expression data sets. Empirical results demonstrate that our method is capable of selecting a proper discrete or categorical attribute to simplify the problem, i.e., the performance of the classifier built for the restructured problem always beats that of the original problem. CONCLUSIONS: The proposed conditional entropy based metric is effective in identifying good partitions of a classification problem, hence enhancing the prediction performance.