Integrated Computational Approaches for Drug Design Targeting Cruzipain.

Cruzipain inhibitors are required after medications to treat Chagas disease because of the need for safer, more effective treatments. Trypanosoma cruzi is the source of cruzipain, a crucial cysteine protease that has driven interest in using computational methods to create more effective inhibitors. We employed a 3D-QSAR model, using a dataset of 36 known inhibitors, and a pharmacophore model to identify potential inhibitors for cruzipain. We also built a deep learning model using the Deep purpose library, trained on 204 active compounds, and validated it with a specific test set. During a comprehensive screening of the Drug Bank database of 8533 molecules, pharmacophore and deep learning models identified 1012 and 340 drug-like molecules, respectively. These molecules were further evaluated through molecular docking, followed by induced-fit docking. Ultimately, molecular dynamics simulation was performed for the final potent inhibitors that exhibited strong binding interactions. These results present four novel cruzipain inhibitors that can inhibit the cruzipain protein of T. cruzi.

Unlocking the therapeutic potential of drug combinations through synergy prediction using graph transformer networks.

Drug combinations are frequently used to treat cancer to reduce side effects and increase efficacy. The experimental discovery of drug combination synergy is time-consuming and expensive for large datasets. Therefore, an efficient and reliable computational approach is required to investigate these drug combinations. Advancements in deep learning can handle large datasets with various biological problems. In this study, we developed a SynergyGTN model based on the Graph Transformer Network to predict the synergistic drug combinations against an untreated cancer cell line expression profile. We represent the drug via a graph, with each node and edge of the graph containing nine types of atomic feature vectors and four bonds features, respectively. The cell lines represent based on their gene expression profiles. The drug graph was passed through the GTN layers to extract a generalized feature map for each drug pairs. The drug pair extracted features and cell-line gene expression profiles were concatenated and subsequently subjected to processing through multiple densely connected layers. SynergyGTN outperformed the state-of-the-art methods, with a receiver operating characteristic area under the curve improvement of 5% on the 5-fold cross-validation. The accuracy of SynergyGTN was further verified through three types of cross-validation tests strategies namely leave-drug-out, leave-combination-out, and leave-tissue-out, resulting in improvement in accuracy of 8%, 1%, and 2%, respectively. The Astrazeneca Dream dataset was utilized as an independent dataset to validate and assess the generalizability of the proposed method, resulting in an improvement in balanced accuracy of 13%. In conclusion, SynergyGTN is a reliable and efficient computational approach for predicting drug combination synergy in cancer treatment. Finally, we developed a web server tool to facilitate the pharmaceutical industry and researchers, as available at: http://nsclbio.jbnu.ac.kr/tools/SynergyGTN/.

Identification of Functional piRNAs Using a Convolutional Neural Network.

Piwi-interacting RNAs (piRNAs) are a distinct sub-class of small non-coding RNAs that are mainly responsible for germline stem cell maintenance, gene stability, and maintaining genome integrity by repression of transposable elements. piRNAs are also expressed aberrantly and associated with various kinds of cancers. To identify piRNAs and their role in guiding target mRNA deadenylation, the currently available computational methods require urgent improvements in performance. To facilitate this, we propose a robust predictor based on a lightweight and simplified deep learning architecture using a convolutional neural network (CNN) to extract significant features from raw RNA sequences without the need for more customized features. The proposed model's performance is comprehensively evaluated using k-fold cross-validation on a benchmark dataset. The proposed model significantly outperforms existing computational methods in the prediction of piRNAs and their role in target mRNA deadenylation. In addition, a user-friendly and publicly-accessible web server is available at http://nsclbio.jbnu.ac.kr/tools/2S-piRCNN/.

i4mC-Deep: An Intelligent Predictor of N4-Methylcytosine Sites Using a Deep Learning Approach with Chemical Properties.

DNA is subject to epigenetic modification by the molecule N4-methylcytosine (4mC). N4-methylcytosine plays a crucial role in DNA repair and replication, protects host DNA from degradation, and regulates DNA expression. However, though current experimental techniques can identify 4mC sites, such techniques are expensive and laborious. Therefore, computational tools that can predict 4mC sites would be very useful for understanding the biological mechanism of this vital type of DNA modification. Conventional machine-learning-based methods rely on hand-crafted features, but the new method saves time and computational cost by making use of learned features instead. In this study, we propose i4mC-Deep, an intelligent predictor based on a convolutional neural network (CNN) that predicts 4mC modification sites in DNA samples. The CNN is capable of automatically extracting important features from input samples during training. Nucleotide chemical properties and nucleotide density, which together represent a DNA sequence, act as CNN input data. The outcome of the proposed method outperforms several state-of-the-art predictors. When i4mC-Deep was used to analyze G. subterruneus DNA, the accuracy of the results was improved by 3.9% and MCC increased by 10.5% compared to a conventional predictor.

XG-ac4C: identification of N4-acetylcytidine (ac4C) in mRNA using eXtreme gradient boosting with electron-ion interaction pseudopotentials.

N4-acetylcytidine (ac4C) is a post-transcriptional modification in mRNA which plays a major role in the stability and regulation of mRNA translation. The working mechanism of ac4C modification in mRNA is still unclear and traditional laboratory experiments are time-consuming and expensive. Therefore, we propose an XG-ac4C machine learning model based on the eXtreme Gradient Boost classifier for the identification of ac4C sites. The XG-ac4C model uses a combination of electron-ion interaction pseudopotentials and electron-ion interaction pseudopotentials of trinucleotide of the nucleotides in ac4C sites. Moreover, Shapley additive explanations and local interpretable model-agnostic explanations are applied to understand the importance of features and their contribution to the final prediction outcome. The obtained results demonstrate that XG-ac4C outperforms existing state-of-the-art methods. In more detail, the proposed model improves the area under the precision-recall curve by 9.4% and 9.6% in cross-validation and independent tests, respectively. Finally, a user-friendly web server based on the proposed model for ac4C site identification is made freely available at http://nsclbio.jbnu.ac.kr/tools/xgac4c/ .