Accelerating drug discovery for glucocorticoid receptor (GR)-related disorders, including innovative machine learning (ML)-based approaches, holds promise in advancing therapeutic development, optimizing treatment efficacy, and mitigating adverse effects. While experimental methods can accurately identify GR antagonists, they are often not cost-effective for large-scale drug discovery. Thus, computational approaches leveraging SMILES information for precise in silico identification of GR antagonists are crucial, enabling efficient and scalable drug discovery. Here, we develop a new ensemble learning approach using a multi-step stacking strategy (M3S), termed M3S-GRPred, aimed at rapidly and accurately discovering novel GR antagonists. To the best of our knowledge, M3S-GRPred is the first SMILES-based predictor designed to identify GR antagonists without the use of 3D structural information. In M3S-GRPred, we first constructed different balanced subsets using an under-sampling approach. Using these balanced subsets, we explored and evaluated heterogeneous base-classifiers trained with a variety of SMILES-based feature descriptors coupled with popular ML algorithms. Finally, M3S-GRPred was constructed by integrating probabilistic feature from the selected base-classifiers derived from a two-step feature selection technique. Our comparative experiments demonstrate that M3S-GRPred can precisely identify GR antagonists and effectively address the imbalanced dataset. Compared to traditional ML classifiers, M3S-GRPred attained superior performance in terms of both the training and independent test datasets. Additionally, M3S-GRPred was applied to identify potential GR antagonists among FDA-approved drugs confirmed through molecular docking, followed by detailed MD simulation studies for drug repurposing in Cushing's syndrome. We anticipate that M3S-GRPred will serve as an efficient screening tool for discovering novel GR antagonists from vast libraries of unknown compounds in a cost-effective manner.

Epigenetics encompasses dynamic and reversible modifications that regulate gene activity without altering the underlying DNA sequence. Epigenetic processes, including non-coding RNA interactions, and DNA methylation regulate patterns of gene expression by responding to cellular signaling, environmental stimuli, and developmental cues. The balance of histone acetylation is maintained by histone deacetylase (HDAC) and histone acetyltransferase (HAT) activities. Aberrant HDAC upregulation, often seen in cancer cells, disrupts this balance. HDAC inhibitors (HDACi) are thus used in cancer treatment. However, most synthetic HDACis are not specific to HDAC classes or individual members, highlighting the need for highly selective HDAC inhibitors. Machine learning (ML)-driven methods are now recognized as rapid and cost-efficient tools in drug discovery and development, capable of identifying inhibitors solely from SMILES notation, without requiring the 3D ligand structure. Here, we present a novel and interpretable deep learning-based framework, DeepHDAC3i, for accurate in silico identification of HDAC3i using only the SMILES notation. Firstly, we employed five molecular encoding methods, namely CDKExt, KR, KRC, Pubchem, and RDKIT, to extract the biological and structural information in HDAC3i. These molecular representations were then fused to generate multi-view features. Secondly, elastic net was employed to determine the optimal feature subset and enhance prediction performance. Thirdly, a one-dimensional convolutional neural network (1D-CNN) coupled with the optimal feature set was chosen for the construction of the final model. Finally, our framework leveraged the Shapley Additive exPlanation algorithm to disclose the most important features for identifying HDAC3i. On the independent test dataset, DeepHDAC3i achieved an accuracy of 0.965, MCC of 0.930, and AUC of 0.985, which were significantly higher than several conventional machine learning and deep learning models. In addition, upon comparison with the existing methods, DeepHDAC3i secured the best performance with improvements of approximately 4.80, 4.70, 6.50, and 9.50% in accuracy, F1, AUC, and MCC, respectively. Taken together, DeepHDAC3i is superior to other compared models and can be a useful tool for precisely identifying HDAC3i.

Methicillin-resistant S. aureus (MRSA) has prominently emerged among the recognized causes of community-acquired and hospital infections. We proposed a novel computational approach, iMRSA-Fuse, based on a multi-view feature fusion strategy for fast and accurate anti-MRSA peptide identification. In iMRSA-Fuse, we explored and integrated 12 different sequence-based feature descriptors from multiple perspectives, in conjunction with 12 popular machine learning (ML) algorithms, to construct multi-view features that were able to fully capture the useful information of anti-MRSA peptides. Additionally, we applied our customized genetic algorithm to determine a set of multi-view features to enhance its discriminative ability. Based on a series of comparative results, our multi-view features exhibited the most discriminative ability compared to several conventional feature descriptors. Moreover, concerning the independent test dataset, iMRSA-Fuse achieved the best balanced accuracy (BACC) and Matthew's correlation coefficient (MCC) of 0.997 and 0.981, respectively with an increase of 3.93 and 7.78%, respectively. Finally, to facilitate the large-scale identification of candidate anti-MRSA peptides, a user-friendly web server of the iMRSA-Fuse model is constructed and is freely accessible at https://pmlabqsar.pythonanywhere.com/iMRSA-Fuse. We anticipate that this new computational approach will be effectively applied to screen and prioritize candidate peptides that might exhibit the great anti-MRSA activities.

Non-coding RNAs (ncRNAs) are a class of RNA molecules that do not have the potential to encode proteins. Meanwhile, they can occupy a significant portion of the human genome and participate in gene expression regulation through various mechanisms. Gestational diabetes mellitus (GDM) is a pathologic condition of carbohydrate intolerance that begins or is first detected during pregnancy, making it one of the most common pregnancy complications. Although the exact pathogenesis of GDM remains unclear, several recent studies have shown that ncRNAs play a crucial regulatory role in GDM. Herein, we present a comprehensive review on the multiple mechanisms of ncRNAs in GDM along with their potential role as biomarkers. In addition, we investigate the contribution of deep learning-based models in discovering disease-specific ncRNA biomarkers and elucidate the underlying mechanisms of ncRNA. This might assist community-wide efforts to obtain insights into the regulatory mechanisms of ncRNAs in disease and guide a novel approach for early diagnosis and treatment of disease.

BACKGROUND: Tyrosinase is an enzyme involved in melanin production in the skin. Several hyperpigmentation disorders involve the overproduction of melanin and instability of tyrosinase activity resulting in darker, discolored patches on the skin. Therefore, discovering tyrosinase inhibitory peptides (TIPs) is of great significance for basic research and clinical treatments. However, the identification of TIPs using experimental methods is generally cost-ineffective and time-consuming. RESULTS: Herein, a stacked ensemble learning approach, called TIPred, is proposed for the accurate and quick identification of TIPs by using sequence information. TIPred explored a comprehensive set of various baseline models derived from well-known machine learning (ML) algorithms and heterogeneous feature encoding schemes from multiple perspectives, such as chemical structure properties, physicochemical properties, and composition information. Subsequently, 130 baseline models were trained and optimized to create new probabilistic features. Finally, the feature selection approach was utilized to determine the optimal feature vector for developing TIPred. Both tenfold cross-validation and independent test methods were employed to assess the predictive capability of TIPred by using the stacking strategy. Experimental results showed that TIPred significantly outperformed the state-of-the-art method in terms of the independent test, with an accuracy of 0.923, MCC of 0.757 and an AUC of 0.977. CONCLUSIONS: The proposed TIPred approach could be a valuable tool for rapidly discovering novel TIPs and effectively identifying potential TIP candidates for follow-up experimental validation. Moreover, an online webserver of TIPred is publicly available at http://pmlabstack.pythonanywhere.com/TIPred .

BACKGROUND: The identification of tumor T cell antigens (TTCAs) is crucial for providing insights into their functional mechanisms and utilizing their potential in anticancer vaccines development. In this context, TTCAs are highly promising. Meanwhile, experimental technologies for discovering and characterizing new TTCAs are expensive and time-consuming. Although many machine learning (ML)-based models have been proposed for identifying new TTCAs, there is still a need to develop a robust model that can achieve higher rates of accuracy and precision. RESULTS: In this study, we propose a new stacking ensemble learning-based framework, termed StackTTCA, for accurate and large-scale identification of TTCAs. Firstly, we constructed 156 different baseline models by using 12 different feature encoding schemes and 13 popular ML algorithms. Secondly, these baseline models were trained and employed to create a new probabilistic feature vector. Finally, the optimal probabilistic feature vector was determined based the feature selection strategy and then used for the construction of our stacked model. Comparative benchmarking experiments indicated that StackTTCA clearly outperformed several ML classifiers and the existing methods in terms of the independent test, with an accuracy of 0.932 and Matthew's correlation coefficient of 0.866. CONCLUSIONS: In summary, the proposed stacking ensemble learning-based framework of StackTTCA could help to precisely and rapidly identify true TTCAs for follow-up experimental verification. In addition, we developed an online web server ( http://2pmlab.camt.cmu.ac.th/StackTTCA ) to maximize user convenience for high-throughput screening of novel TTCAs.

MOTIVATION: Therapeutic peptides failing at clinical trials could be attributed to their toxicity profiles like hemolytic activity, which hamper further progress of peptides as drug candidates. The accurate prediction of hemolytic peptides (HLPs) and its activity from the given peptides is one of the challenging tasks in immunoinformatics, which is essential for drug development and basic research. Although there are a few computational methods that have been proposed for this aspect, none of them are able to identify HLPs and their activities simultaneously. RESULTS: In this study, we proposed a two-layer prediction framework, called HLPpred-Fuse, that can accurately and automatically predict both hemolytic peptides (HLPs or non-HLPs) as well as HLPs activity (high and low). More specifically, feature representation learning scheme was utilized to generate 54 probabilistic features by integrating six different machine learning classifiers and nine different sequence-based encodings. Consequently, the 54 probabilistic features were fused to provide sufficiently converged sequence information which was used as an input to extremely randomized tree for the development of two final prediction models which independently identify HLP and its activity. Performance comparisons over empirical cross-validation analysis, independent test and case study against state-of-the-art methods demonstrate that HLPpred-Fuse consistently outperformed these methods in the identification of hemolytic activity. AVAILABILITY AND IMPLEMENTATION: For the convenience of experimental scientists, a web-based tool has been established at http://thegleelab.org/HLPpred-Fuse. CONTACT: [email protected] or [email protected] or [email protected]. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.