Unraveling the bioactivity of anticancer peptides as deduced from machine learning

Cancer imposes a global health burden as it represents one of the leading causes of morbidity and mortality while also giving rise to significant economic burden owing to the associated expenditures for its monitoring and treatment. In spite of advancements in cancer therapy, the low success rate and recurrence of tumor has necessitated the ongoing search for new therapeutic agents. Aside from drugs based on small molecules and protein-based biopharmaceuticals, there has been an intense effort geared towards the development of peptide-based therapeutics owing to its favorable and intrinsic properties of being relatively small, highly selective, potent, safe and low in production costs. In spite of these advantages, there are several inherent weaknesses that are in need of attention in the design and development of therapeutic peptides. An abundance of data on bioactive and therapeutic peptides have been accumulated over the years and the burgeoning area of artificial intelligence has set the stage for the lucrative utilization of machine learning to make sense of these large and high-dimensional data. This review summarizes the current state-of-the-art on the application of machine learning for studying the bioactivity of anticancer peptides along with future outlook of the field. Data and R codes used in the analysis herein are available on GitHub at https://github.com/Shoombuatong2527/anticancer-peptides-review

Prediction of aromatase inhibitory activity using the efficient linear method (ELM)

Aromatase inhibition is an effective treatment strategy for breast cancer. Currently, several in silico methods have been developed for the prediction of aromatase inhibitors (AIs) using artificial neural network (ANN) or support vector machine (SVM). In spite of this, there are ample opportunities for further improvements by developing a simple and interpretable quantitative structure-activity relationship (QSAR) method. Herein, an efficient linear method (ELM) is proposed for constructing a highly predictive QSAR model containing a spontaneous feature importance estimator. Briefly, ELM is a linear-based model with optimal parameters derived from genetic algorithm. Results showed that the simple ELM method displayed robust performance with 10-fold cross-validation MCC values of 0.64 and 0.56 for steroidal and non-steroidal AIs, respectively. Comparative analyses with other machine learning methods (i.e. ANN, SVM and decision tree) were also performed. A thorough analysis of informative molecular descriptors for both steroidal and non-steroidal AIs provided insights into the mechanism of action of compounds. Our findings suggest that the shape and polarizability of compounds may govern the inhibitory activity of both steroidal and non-steroidal types whereas the terminal primary C(sp3) functional group and electronegativity may be required for non-steroidal AIs. The R code of the ELM method is available at http://dx.doi.org/10.6084/m9.figshare.1274030

Classification of P-glycoprotein-interacting compounds using machine learning methods

P-glycoprotein (Pgp) is a drug transporter that plays important roles in multidrug resistance and drug pharmacokinetics. The inhibition of Pgp has become a notable strategy for combating multidrug-resistant cancers and improving therapeutic outcomes. However, the polyspecific nature of Pgp, together with inconsistent results in experimental assays, renders the determination of endpoints for Pgp-interacting compounds a great challenge. In this study, the classification of a large set of 2,477 Pgp-interacting compounds (i.e., 1341 inhibitors, 913 noninhibitors, 197 substrates and 26 non-substrates) was performed using several machine learning methods (i.e., decision tree induction, artificial neural network modelling and support vector machine) as a function of their physicochemical properties. The models provided good predictive performance, producing MCC values in the range of 0.739-1 for internal cross-validation and 0.665-1 for external validation. The study provided simple and interpretable models for important properties that influence the activity of Pgp-interacting compounds, which are potentially beneficial for screening and rational design of Pgp inhibitors that are of clinical importance

iBitter-Fuse: A Novel Sequence-Based Bitter Peptide Predictor by Fusing Multi-View Features.

Accurate identification of bitter peptides is of great importance for better understanding their biochemical and biophysical properties. To date, machine learning-based methods have become effective approaches for providing a good avenue for identifying potential bitter peptides from large-scale protein datasets. Although few machine learning-based predictors have been developed for identifying the bitterness of peptides, their prediction performances could be improved. In this study, we developed a new predictor (named iBitter-Fuse) for achieving more accurate identification of bitter peptides. In the proposed iBitter-Fuse, we have integrated a variety of feature encoding schemes for providing sufficient information from different aspects, namely consisting of compositional information and physicochemical properties. To enhance the predictive performance, the customized genetic algorithm utilizing self-assessment-report (GA-SAR) was employed for identifying informative features followed by inputting optimal ones into a support vector machine (SVM)-based classifier for developing the final model (iBitter-Fuse). Benchmarking experiments based on both 10-fold cross-validation and independent tests indicated that the iBitter-Fuse was able to achieve more accurate performance as compared to state-of-the-art methods. To facilitate the high-throughput identification of bitter peptides, the iBitter-Fuse web server was established and made freely available online. It is anticipated that the iBitter-Fuse will be a useful tool for aiding the discovery and de novo design of bitter peptides

SCMTHP: A New Approach for Identifying and Characterizing of Tumor-Homing Peptides Using Estimated Propensity Scores of Amino Acids.

Tumor-homing peptides (THPs) are small peptides that can recognize and bind cancer cells specifically. To gain a better understanding of THPs' functional mechanisms, the accurate identification and characterization of THPs is required. Although some computational methods for in silico THP identification have been proposed, a major drawback is their lack of model interpretability. In this study, we propose a new, simple and easily interpretable computational approach (called SCMTHP) for identifying and analyzing tumor-homing activities of peptides via the use of a scoring card method (SCM). To improve the predictability and interpretability of our predictor, we generated propensity scores of 20 amino acids as THPs. Finally, informative physicochemical properties were used for providing insights on characteristics giving rise to the bioactivity of THPs via the use of SCMTHP-derived propensity scores. Benchmarking experiments from independent test indicated that SCMTHP could achieve comparable performance to state-of-the-art method with accuracies of 0.827 and 0.798, respectively, when evaluated on two benchmark datasets consisting of Main and Small datasets. Furthermore, SCMTHP was found to outperform several well-known machine learning-based classifiers (e.g., decision tree, k-nearest neighbor, multi-layer perceptron, naive Bayes and partial least squares regression) as indicated by both 10-fold cross-validation and independent tests. Finally, the SCMTHP web server was established and made freely available online. SCMTHP is expected to be a useful tool for rapid and accurate identification of THPs and for providing better understanding on THP biophysical and biochemical properties

SCORPION is a stacking-based ensemble learning framework for accurate prediction of phage virion proteins.

Funder: Mahidol UniversityFunder: College of Arts, Media and Technology, Chiang Mai UniversityFunder: Chiang Mai UniversityFunder: Information Technology Service Center (ITSC) of Chiang Mai UniversityFast and accurate identification of phage virion proteins (PVPs) would greatly aid facilitation of antibacterial drug discovery and development. Although, several research efforts based on machine learning (ML) methods have been made for in silico identification of PVPs, these methods have certain limitations. Therefore, in this study, we propose a new computational approach, termed SCORPION, (StaCking-based Predictior fOR Phage VIrion PrOteiNs), to accurately identify PVPs using only protein primary sequences. Specifically, we explored comprehensive 13 different feature descriptors from different aspects (i.e., compositional information, composition-transition-distribution information, position-specific information and physicochemical properties) with 10 popular ML algorithms to construct a pool of optimal baseline models. These optimal baseline models were then used to generate probabilistic features (PFs) and considered as a new feature vector. Finally, we utilized a two-step feature selection strategy to determine the optimal PF feature vector and used this feature vector to develop a stacked model (SCORPION). Both tenfold cross-validation and independent test results indicate that SCORPION achieves superior predictive performance than its constitute baseline models and existing methods. We anticipate SCORPION will serve as a useful tool for the cost-effective and large-scale screening of new PVPs. The source codes and datasets for this work are available for downloading in the GitHub repository ( https://github.com/saeed344/SCORPION )

The MicroRNA Interaction Network of Lipid Diseases

Background: Dyslipidemia is one of the major forms of lipid disorder, characterized by increased triglycerides (TGs), increased low-density lipoprotein-cholesterol (LDL-C), and decreased high-density lipoprotein-cholesterol (HDL-C) levels in blood. Recently, MicroRNAs (miRNAs) have been reported to involve in various biological processes; their potential usage being a biomarkers and in diagnosis of various diseases. Computational approaches including text mining have been used recently to analyze abstracts from the public databases to observe the relationships/associations between the biological molecules, miRNAs, and disease phenotypes.Materials and Methods: In the present study, significance of text mined extracted pair associations (miRNA-lipid disease) were estimated by one-sided Fisher's exact test. The top 20 significant miRNA-disease associations were visualized on Cytoscape. The CyTargetLinker plug-in tool on Cytoscape was used to extend the network and predicts new miRNA target genes. The Biological Networks Gene Ontology (BiNGO) plug-in tool on Cytoscape was used to retrieve gene ontology (GO) annotations for the targeted genes.Results: We retrieved 227 miRNA-lipid disease associations including 148 miRNAs. The top 20 significant miRNAs analysis on CyTargetLinker provides defined, predicted and validated gene targets, further targeted genes analyzed by BiNGO showed targeted genes were significantly associated with lipid, cholesterol, apolipoprotein, and fatty acids GO terms.Conclusion: We are the first to provide a reliable miRNA-lipid disease association network based on text mining. This could help future experimental studies that aim to validate predicted gene targets

StackER: a novel SMILES-based stacked approach for the accelerated and efficient discovery of ERα and ERβ antagonists

Abstract The role of estrogen receptors (ERs) in breast cancer is of great importance in both clinical practice and scientific exploration. However, around 15–30% of those affected do not see benefits from the usual treatments owing to the innate resistance mechanisms, while 30–40% will gain resistance through treatments. In order to address this problem and facilitate community-wide efforts, machine learning (ML)-based approaches are considered one of the most cost-effective and large-scale identification methods. Herein, we propose a new SMILES-based stacked approach, termed StackER, for the accelerated and efficient identification of ERα and ERβ inhibitors. In StackER, we first established an up-to-date dataset consisting of 1,996 and 1,207 compounds for ERα and ERβ, respectively. Using the up-to-date dataset, StackER explored a wide range of different SMILES-based feature descriptors and ML algorithms in order to generate probabilistic features (PFs). Finally, the selected PFs derived from the two-step feature selection strategy were used for the development of an efficient stacked model. Both cross-validation and independent tests showed that StackER surpassed several conventional ML classifiers and the existing method in precisely predicting ERα and ERβ inhibitors. Remarkably, StackER achieved MCC values of 0.829–0.847 and 0.712–0.786 in terms of the cross-validation and independent tests, respectively, which were 5.92–8.29 and 1.59–3.45% higher than the existing method. In addition, StackER was applied to determine useful features for being ERα and ERβ inhibitors and identify FDA-approved drugs as potential ERα inhibitors in efforts to facilitate drug repurposing. This innovative stacked method is anticipated to facilitate community-wide efforts in efficiently narrowing down ER inhibitor screening

DeepAR: a novel deep learning-based hybrid framework for the interpretable prediction of androgen receptor antagonists

Abstract Drug resistance represents a major obstacle to therapeutic innovations and is a prevalent feature in prostate cancer (PCa). Androgen receptors (ARs) are the hallmark therapeutic target for prostate cancer modulation and AR antagonists have achieved great success. However, rapid emergence of resistance contributing to PCa progression is the ultimate burden of their long-term usage. Hence, the discovery and development of AR antagonists with capability to combat the resistance, remains an avenue for further exploration. Therefore, this study proposes a novel deep learning (DL)-based hybrid framework, named DeepAR, to accurately and rapidly identify AR antagonists by using only the SMILES notation. Specifically, DeepAR is capable of extracting and learning the key information embedded in AR antagonists. Firstly, we established a benchmark dataset by collecting active and inactive compounds against AR from the ChEMBL database. Based on this dataset, we developed and optimized a collection of baseline models by using a comprehensive set of well-known molecular descriptors and machine learning algorithms. Then, these baseline models were utilized for creating probabilistic features. Finally, these probabilistic features were combined and used for the construction of a meta-model based on a one-dimensional convolutional neural network. Experimental results indicated that DeepAR is a more accurate and stable approach for identifying AR antagonists in terms of the independent test dataset, by achieving an accuracy of 0.911 and MCC of 0.823. In addition, our proposed framework is able to provide feature importance information by leveraging a popular computational approach, named SHapley Additive exPlanations (SHAP). In the meanwhile, the characterization and analysis of potential AR antagonist candidates were achieved through the SHAP waterfall plot and molecular docking. The analysis inferred that N-heterocyclic moieties, halogenated substituents, and a cyano functional group were significant determinants of potential AR antagonists. Lastly, we implemented an online web server by using DeepAR (at http://pmlabstack.pythonanywhere.com/DeepAR ). We anticipate that DeepAR could be a useful computational tool for community-wide facilitation of AR candidates from a large number of uncharacterized compounds

TIPred: a novel stacked ensemble approach for the accelerated discovery of tyrosinase inhibitory peptides

Abstract 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