Searching for potential inhibitors of SARS-COV-2 main protease using supervised learning and perturbation calculations.

Inhibiting the biological activity of SARS-CoV-2 Mpro can prevent viral replication. In this context, a hybrid approach using knowledge- and physics-based methods was proposed to characterize potential inhibitors for SARS-CoV-2 Mpro. Initially, supervised machine learning (ML) models were trained to predict a ligand-binding affinity of ca. 2 million compounds with the correlation on a test set of R = 0.748 ± 0.044 . Atomistic simulations were then used to refine the outcome of the ML model. Using LIE/FEP calculations, nine compounds from the top 100 ML inhibitors were suggested to bind well to the protease with the domination of van der Waals interactions. Furthermore, the binding affinity of these compounds is also higher than that of nirmatrelvir, which was recently approved by the US FDA to treat COVID-19. In addition, the ligands altered the catalytic triad Cys145 - His41 - Asp187, possibly disturbing the biological activity of SARS-CoV-2.

Future assessment of the impact of the COVID-19 pandemic on the electricity market based on a stochastic socioeconomic model.

This paper proposes a time-series stochastic socioeconomic model for analyzing the impact of the pandemic on the regulated distribution electricity market. The proposed methodology combines the optimized tariff model (socioeconomic market model) and the random walk concept (risk assessment technique) to ensure robustness/accuracy. The model enables both a past and future analysis of the impact of the pandemic, which is essential to prepare regulatory agencies beforehand and allow enough time for the development of efficient public policies. By applying it to six Brazilian concession areas, results demonstrate that consumers have been/will be heavily affected in general, mainly due to the high electricity tariffs that took place with the pandemic, overcoming the natural trend of the market. In contrast, the model demonstrates that the pandemic did not/will not significantly harm power distribution companies in general, mainly due to the loan granted by the regulator agency, named COVID-account. Socioeconomic welfare losses averaging 500 (MR$/month) are estimated for the equivalent concession area, i.e., the sum of the six analyzed concession areas. Furthermore, this paper proposes a stochastic optimization problem to mitigate the impact of the pandemic on the electricity market over time, considering the interests of consumers, power distribution companies, and the government. Results demonstrate that it is successful as the tariffs provided by the algorithm compensate for the reduction in demand while increasing the socioeconomic welfare of the market.

Deep features to detect pulmonary abnormalities in chest X-rays due to infectious diseaseX: Covid-19, pneumonia, and tuberculosis.

Chest X-ray (CXR) imaging is a low-cost, easy-to-use imaging alternative that can be used to diagnose/screen pulmonary abnormalities due to infectious diseaseX: Covid-19, Pneumonia and Tuberculosis (TB). Not limited to binary decisions (with respect to healthy cases) that are reported in the state-of-the-art literature, we also consider non-healthy CXR screening using a lightweight deep neural network (DNN) with a reduced number of epochs and parameters. On three diverse publicly accessible and fully categorized datasets, for non-healthy versus healthy CXR screening, the proposed DNN produced the following accuracies: 99.87% on Covid-19 versus healthy, 99.55% on Pneumonia versus healthy, and 99.76% on TB versus healthy datasets. On the other hand, when considering non-healthy CXR screening, we received the following accuracies: 98.89% on Covid-19 versus Pneumonia, 98.99% on Covid-19 versus TB, and 100% on Pneumonia versus TB. To further precisely analyze how well the proposed DNN worked, we considered well-known DNNs such as ResNet50, ResNet152V2, MobileNetV2, and InceptionV3. Our results are comparable with the current state-of-the-art, and as the proposed CNN is light, it could potentially be used for mass screening in resource-constraint regions.

Deep learning and machine learning-based voice analysis for the detection of COVID-19: A proposal and comparison of architectures.

Alongside the currently used nasal swab testing, the COVID-19 pandemic situation would gain noticeable advantages from low-cost tests that are available at any-time, anywhere, at a large-scale, and with real time answers. A novel approach for COVID-19 assessment is adopted here, discriminating negative subjects versus positive or recovered subjects. The scope is to identify potential discriminating features, highlight mid and short-term effects of COVID on the voice and compare two custom algorithms. A pool of 310 subjects took part in the study; recordings were collected in a low-noise, controlled setting employing three different vocal tasks. Binary classifications followed, using two different custom algorithms. The first was based on the coupling of boosting and bagging, with an AdaBoost classifier using Random Forest learners. A feature selection process was employed for the training, identifying a subset of features acting as clinically relevant biomarkers. The other approach was centered on two custom CNN architectures applied to mel-Spectrograms, with a custom knowledge-based data augmentation. Performances, evaluated on an independent test set, were comparable: Adaboost and CNN differentiated COVID-19 positive from negative with accuracies of 100% and 95% respectively, and recovered from negative individuals with accuracies of 86.1% and 75% respectively. This study highlights the possibility to identify COVID-19 positive subjects, foreseeing a tool for on-site screening, while also considering recovered subjects and the effects of COVID-19 on the voice. The two proposed novel architectures allow for the identification of biomarkers and demonstrate the ongoing relevance of traditional ML versus deep learning in speech analysis.

Real-time data of COVID-19 detection with IoT sensor tracking using artificial neural network.

The coronavirus pandemic has affected people all over the world and posed a great challenge to international health systems. To aid early detection of coronavirus disease-2019 (COVID-19), this study proposes a real-time detection system based on the Internet of Things framework. The system collects real-time data from users to determine potential coronavirus cases, analyses treatment responses for people who have been treated, and accurately collects and analyses the datasets. Artificial intelligence-based algorithms are an alternative decision-making solution to extract valuable information from clinical data. This study develops a deep learning optimisation system that can work with imbalanced datasets to improve the classification of patients. A synthetic minority oversampling technique is applied to solve the problem of imbalance, and a recursive feature elimination algorithm is used to determine the most effective features. After data balance and extraction of features, the data are split into training and testing sets for validating all models. The experimental predictive results indicate good stability and compatibility of the models with the data, providing maximum accuracy of 98% and precision of 97%. Finally, the developed models are demonstrated to handle data bias and achieve high classification accuracy for patients with COVID-19. The findings of this study may be useful for healthcare organisations to properly prioritise assets.

The relationship between air pollution and COVID-19-related deaths: An application to three French cities.

Being heavily dependent to oil products (mainly gasoline and diesel), the French transport sector is the main emitter of Particulate Matter (PMs) whose critical levels induce harmful health effects for urban inhabitants. We selected three major French cities (Paris, Lyon, and Marseille) to investigate the relationship between the Coronavirus Disease 19 (COVID-19) outbreak and air pollution. Using Artificial Neural Networks (ANNs) experiments, we have determined the concentration of PM2.5 and PM10 linked to COVID-19-related deaths. Our focus is on the potential effects of Particulate Matter (PM) in spreading the epidemic. The underlying hypothesis is that a pre-determined particulate concentration can foster COVID-19 and make the respiratory system more susceptible to this infection. The empirical strategy used an innovative Machine Learning (ML) methodology. In particular, through the so-called cutting technique in ANNs, we found new threshold levels of PM2.5 and PM10 connected to COVID-19: 17.4 µg/m3 (PM2.5) and 29.6 µg/m3 (PM10) for Paris; 15.6 µg/m3 (PM2.5) and 20.6 µg/m3 (PM10) for Lyon; 14.3 µg/m3 (PM2.5) and 22.04 µg/m3 (PM10) for Marseille. Interestingly, all the threshold values identified by the ANNs are higher than the limits imposed by the European Parliament. Finally, a Causal Direction from Dependency (D2C) algorithm is applied to check the consistency of our findings.

A comparison of statistical and machine-learning techniques in evaluating the association between dietary patterns and 10-year cardiometabolic risk (2002-2012): the ATTICA study.

Statistical methods are usually applied in examining diet-disease associations, whereas factor analysis is commonly used for dietary pattern recognition. Recently, machine learning (ML) has been also proposed as an alternative technique in health classification. In this work, the predictive accuracy of statistical v. ML methodologies as regards the association of dietary patterns on CVD risk was tested. During 2001-2002, 3042 men and women (45 (sd 14) years) were enrolled in the ATTICA study. In 2011-2012, the 10-year CVD follow-up was performed among 2020 participants. Item Response Theory was applied to create a metric of combined 10-year cardiometabolic risk, the 'Cardiometabolic Health Score', that incorporated incidence of CVD, diabetes, hypertension and hypercholesterolaemia. Factor analysis was performed to extract dietary patterns, on the basis of either foods or nutrients consumed; linear regression analysis was used to assess their association with the cardiometabolic score. Two ML techniques (k-nearest-neighbor's algorithm and random-forests decision tree) were applied to evaluate participants' health based on dietary information. Factor analysis revealed five and three factors from foods and nutrients, respectively, explaining 54 and 65 % of the total variation in intake. Nutrient and food pattern regression models showed similar accuracy in correctly classifying an individual according to the cardiometabolic risk (R 2=9·6 % and R 2=8·3 %, respectively). ML techniques were superior compared with linear regression in correct classification of the individuals according to the Health Score (accuracy approximately 38 v. 6 %, respectively), whereas the two ML methods showed equal classification ability. Conclusively, ML methods could be a valuable tool in the field of nutritional epidemiology, leading to more accurate disease-risk evaluation.

Knowledge, attitude, and practice of artificial intelligence among medical students in Sudan: a cross-sectional study.

Introduction: In this cross-sectional study, the authors explored the knowledge, attitudes, and practices related to artificial intelligence (AI) among medical students in Sudan. With AI increasingly impacting healthcare, understanding its integration into medical education is crucial. This study aimed to assess the current state of AI awareness, perceptions, and practical experiences among medical students in Sudan. The authors aimed to evaluate the extent of AI familiarity among Sudanese medical students by examining their attitudes toward its application in medicine. Additionally, this study seeks to identify the factors influencing knowledge levels and explore the practical implementation of AI in the medical field. Method: A web-based survey was distributed to medical students in Sudan via social media platforms and e-mail during October 2023. The survey included questions on demographic information, knowledge of AI, attitudes toward its applications, and practical experiences. The descriptive statistics, χ2 tests, logistic regression, and correlations were analyzed using SPSS version 26.0. Results: Out of the 762 participants, the majority exhibited a basic understanding of AI, but detailed knowledge of its applications was limited. Positive attitudes toward the importance of AI in diagnosis, radiology, and pathology were prevalent. However, practical application of these methods was infrequent, with only a minority of the participants having hands-on experience. Factors influencing knowledge included the lack of a formal curriculum and gender disparities. Conclusion: This study highlights the need for comprehensive AI education in medical training programs in Sudan. While participants displayed positive attitudes, there was a notable gap in practical experience. Addressing these gaps through targeted educational interventions is crucial for preparing future healthcare professionals to navigate the evolving landscape of AI in medicine. Recommendations: Policy efforts should focus on integrating AI education into the medical curriculum to ensure readiness for the technological advancements shaping the future of healthcare.

Direct Gene Expression Profile Prediction for Uveal Melanoma from Digital Cytopathology Images via Deep Learning and Salient Image Region Identification.

Objective: To demonstrate that deep learning (DL) methods can produce robust prediction of gene expression profile (GEP) in uveal melanoma (UM) based on digital cytopathology images. Design: Evaluation of a diagnostic test or technology. Subjects Participants and Controls: Deidentified smeared cytology slides stained with hematoxylin and eosin obtained from a fine needle aspirated from UM. Methods: Digital whole-slide images were generated by fine-needle aspiration biopsies of UM tumors that underwent GEP testing. A multistage DL system was developed with automatic region-of-interest (ROI) extraction from digital cytopathology images, an attention-based neural network, ROI feature aggregation, and slide-level data augmentation. Main Outcome Measures: The ability of our DL system in predicting GEP on a slide (patient) level. Data were partitioned at the patient level (73% training; 27% testing). Results: In total, our study included 89 whole-slide images from 82 patients and 121 388 unique ROIs. The testing set included 24 slides from 24 patients (12 class 1 tumors; 12 class 2 tumors; 1 slide per patient). Our DL system for GEP prediction achieved an area under the receiver operating characteristic curve of 0.944, an accuracy of 91.7%, a sensitivity of 91.7%, and a specificity of 91.7% on a slide-level analysis. The incorporation of slide-level feature aggregation and data augmentation produced a more predictive DL model (P = 0.0031). Conclusions: Our current work established a complete pipeline for GEP prediction in UM tumors: from automatic ROI extraction from digital cytopathology whole-slide images to slide-level predictions. Our DL system demonstrated robust performance and, if validated prospectively, could serve as an image-based alternative to GEP testing.

Deep Learning in Dermatology: A Systematic Review of Current Approaches, Outcomes, and Limitations.

Artificial intelligence (AI) has recently made great advances in image classification and malignancy prediction in the field of dermatology. However, understanding the applicability of AI in clinical dermatology practice remains challenging owing to the variability of models, image data, database characteristics, and variable outcome metrics. This systematic review aims to provide a comprehensive overview of dermatology literature using convolutional neural networks. Furthermore, the review summarizes the current landscape of image datasets, transfer learning approaches, challenges, and limitations within current AI literature and current regulatory pathways for approval of models as clinical decision support tools.

The applications of machine learning to predict the forming of chemically stable amorphous solid dispersions prepared by hot-melt extrusion.

Amorphous solid dispersion (ASD) is one of the most important strategies to improve the solubility and dissolution rate of poorly water-soluble drugs. As a widely used technique to prepare ASDs, hot-melt extrusion (HME) provides various benefits, including a solvent-free process, continuous manufacturing, and efficient mixing compared to solvent-based methods, such as spray drying. Energy input, consisting of thermal and specific mechanical energy, should be carefully controlled during the HME process to prevent chemical degradation and residual crystallinity. However, a conventional ASD development process uses a trial-and-error approach, which is laborious and time-consuming. In this study, we have successfully built multiple machine learning (ML) models to predict the amorphization of crystalline drug formulations and the chemical stability of subsequent ASDs prepared by the HME process. We utilized 760 formulations containing 49 active pharmaceutical ingredients (APIs) and multiple types of excipients. By evaluating the built ML models, we found that ECFP-LightGBM was the best model to predict amorphization with an accuracy of 92.8%. Furthermore, ECFP-XGBoost was the best in estimating chemical stability with an accuracy of 96.0%. In addition, the feature importance analyses based on SHapley Additive exPlanations (SHAP) and information gain (IG) revealed that several processing parameters and material attributes (i.e., drug loading, polymer ratio, drug's Extended-connectivity fingerprints (ECFP) fingerprints, and polymer's properties) are critical for achieving accurate predictions for the selected models. Moreover, important API's substructures related to amorphization and chemical stability were determined, and the results are largely consistent with the literature. In conclusion, we established the ML models to predict formation of chemically stable ASDs and identify the critical attributes during HME processing. Importantly, the developed ML methodology has the potential to facilitate the product development of ASDs manufactured by HME with a much reduced human workload.

Computational prediction of disordered binding regions.

One of the key features of intrinsically disordered regions (IDRs) is their ability to interact with a broad range of partner molecules. Multiple types of interacting IDRs were identified including molecular recognition fragments (MoRFs), short linear sequence motifs (SLiMs), and protein-, nucleic acids- and lipid-binding regions. Prediction of binding IDRs in protein sequences is gaining momentum in recent years. We survey 38 predictors of binding IDRs that target interactions with a diverse set of partners, such as peptides, proteins, RNA, DNA and lipids. We offer a historical perspective and highlight key events that fueled efforts to develop these methods. These tools rely on a diverse range of predictive architectures that include scoring functions, regular expressions, traditional and deep machine learning and meta-models. Recent efforts focus on the development of deep neural network-based architectures and extending coverage to RNA, DNA and lipid-binding IDRs. We analyze availability of these methods and show that providing implementations and webservers results in much higher rates of citations/use. We also make several recommendations to take advantage of modern deep network architectures, develop tools that bundle predictions of multiple and different types of binding IDRs, and work on algorithms that model structures of the resulting complexes.

Radiomics-Based Assessment of OCT Angiography Images for Diabetic Retinopathy Diagnosis.

Purpose: To evaluate the diagnostic accuracy of machine learning (ML) techniques applied to radiomic features extracted from OCT and OCT angiography (OCTA) images for diabetes mellitus (DM), diabetic retinopathy (DR), and referable DR (R-DR) diagnosis. Design: Cross-sectional analysis of a retinal image dataset from a previous prospective OCTA study (ClinicalTrials.govNCT03422965). Participants: Patients with type 1 DM and controls included in the progenitor study. Methods: Radiomic features were extracted from fundus retinographies, OCT, and OCTA images in each study eye. Logistic regression, linear discriminant analysis, support vector classifier (SVC)-linear, SVC-radial basis function, and random forest models were created to evaluate their diagnostic accuracy for DM, DR, and R-DR diagnosis in all image types. Main Outcome Measures: Area under the receiver operating characteristic curve (AUC) mean and standard deviation for each ML model and each individual and combined image types. Results: A dataset of 726 eyes (439 individuals) were included. For DM diagnosis, the greatest AUC was observed for OCT (0.82, 0.03). For DR detection, the greatest AUC was observed for OCTA (0.77, 0.03), especially in the 3 × 3 mm superficial capillary plexus OCTA scan (0.76, 0.04). For R-DR diagnosis, the greatest AUC was observed for OCTA (0.87, 0.12) and the deep capillary plexus OCTA scan (0.86, 0.08). The addition of clinical variables (age, sex, etc.) improved most models AUC for DM, DR and R-DR diagnosis. The performance of the models was similar in unilateral and bilateral eyes image datasets. Conclusions: Radiomics extracted from OCT and OCTA images allow identification of patients with DM, DR, and R-DR using standard ML classifiers. OCT was the best test for DM diagnosis, OCTA for DR and R-DR diagnosis and the addition of clinical variables improved most models. This pioneer study demonstrates that radiomics-based ML techniques applied to OCT and OCTA images may be an option for DR screening in patients with type 1 DM. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

Personalized predictions of adverse side effects of the COVID-19 vaccines.

Background: Misconceptions about adverse side effects are thought to influence public acceptance of the Coronavirus disease 2019 (COVID-19) vaccines negatively. To address such perceived disadvantages of vaccines, a novel machine learning (ML) approach was designed to generate personalized predictions of the most common adverse side effects following injection of six different COVID-19 vaccines based on personal and health-related characteristics. Methods: Prospective data of adverse side effects following COVID-19 vaccination in 19943 participants from Iran and Switzerland was utilized. Six vaccines were studied: The AZD1222, Sputnik V, BBIBP-CorV, COVAXIN, BNT162b2, and the mRNA-1273 vaccine. The eight side effects were considered as the model output: fever, fatigue, headache, nausea, chills, joint pain, muscle pain, and injection site reactions. The total input parameters for the first and second dose predictions were 46 and 54 features, respectively, including age, gender, lifestyle variables, and medical history. The performances of multiple ML models were compared using Area Under the Receiver Operating Characteristic Curve (ROC-AUC). Results: The total number of people receiving the first dose of the AZD1222, Sputnik V, BBIBP-CorV, COVAXIN, BNT162b2, and mRNA-1273 were 6022, 7290, 5279, 802, 277, and 273, respectively. For the second dose, the numbers were 2851, 5587, 3841, 599, 242 and 228. The Logistic Regression model for predicting different side effects of the first dose achieved ROC-AUCs of 0.620-0.686, 0.685-0.716, 0.632-0.727, 0.527-0.598, 0.548-0.655, 0.545-0.712 for the AZD1222, Sputnik V, BBIBP-CorV, COVAXIN, BNT162b2 and mRNA-1273 vaccines, respectively. The second dose models yielded ROC-AUCs of 0.777-0.867, 0.795-0.848, 0.857-0.906, 0.788-0.875, 0.683-0.850, and 0.486-0.680, respectively. Conclusions: Using a large cohort of recipients vaccinated with COVID-19 vaccines, a novel and personalized strategy was established to predict the occurrence of the most common adverse side effects with high accuracy. This technique can serve as a tool to inform COVID-19 vaccine selection and generate personalized factsheets to curb concerns about adverse side effects.

Machine learning for normal tissue complication probability prediction: Predictive power with versatility and easy implementation.

Background and purpose: A popular Normal tissue Complication (NTCP) model deployed to predict radiotherapy (RT) toxicity is the Lyman-Burman Kutcher (LKB) model of tissue complication. Despite the LKB model's popularity, it can suffer from numerical instability and considers only the generalized mean dose (GMD) to an organ. Machine learning (ML) algorithms can potentially offer superior predictive power of the LKB model, and with fewer drawbacks. Here we examine the numerical characteristics and predictive power of the LKB model and compare these with those of ML. Materials and methods: Both an LKB model and ML models were used to predict G2 Xerostomia on patients following RT for head and neck cancer, using the dose volume histogram of parotid glands as the input feature. Model speed, convergence characteristics and predictive power was evaluated on an independent training set. Results: We found that only global optimization algorithms could guarantee a convergent and predictive LKB model. At the same time our results showed that ML models remained unconditionally convergent and predictive, while staying robust to gradient descent optimization. ML models outperform LKB in Brier score and accuracy but compare to LKB in ROC-AUC. Conclusion: We have demonstrated that ML models can quantify NTCP better than or as well as LKB models, even for a toxicity that the LKB model is particularly well suited to predict. ML models can offer this performance while offering fundamental advantages in model convergence, speed, and flexibility, and so could offer an alternative to the LKB model that could potentially be used in clinical RT planning decisions.

Splicing signature database development to delineate cancer pathways using literature mining and transcriptome machine learning.

Alternative splicing (AS) events modulate certain pathways and phenotypic plasticity in cancer. Although previous studies have computationally analyzed splicing events, it is still a challenge to uncover biological functions induced by reliable AS events from tremendous candidates. To provide essential splicing event signatures to assess pathway regulation, we developed a database by collecting two datasets: (i) reported literature and (ii) cancer transcriptome profile. The former includes knowledge-based splicing signatures collected from 63,229 PubMed abstracts using natural language processing, extracted for 202 pathways. The latter is the machine learning-based splicing signatures identified from pan-cancer transcriptome for 16 cancer types and 42 pathways. We established six different learning models to classify pathway activities from splicing profiles as a learning dataset. Top-ranked AS events by learning model feature importance became the signature for each pathway. To validate our learning results, we performed evaluations by (i) performance metrics, (ii) differential AS sets acquired from external datasets, and (iii) our knowledge-based signatures. The area under the receiver operating characteristic values of the learning models did not exhibit any drastic difference. However, random-forest distinctly presented the best performance to compare with the AS sets identified from external datasets and our knowledge-based signatures. Therefore, we used the signatures obtained from the random-forest model. Our database provided the clinical characteristics of the AS signatures, including survival test, molecular subtype, and tumor microenvironment. The regulation by splicing factors was additionally investigated. Our database for developed signatures supported retrieval and visualization system.

Algorithms for automated diagnosis of cardiovascular diseases based on ECG data: A comprehensive systematic review.

The prevalence of cardiovascular diseases is increasing around the world. However, the technology is evolving and can be monitored with low-cost sensors anywhere at any time. This subject is being researched, and different methods can automatically identify these diseases, helping patients and healthcare professionals with the treatments. This paper presents a systematic review of disease identification, classification, and recognition with ECG sensors. The review was focused on studies published between 2017 and 2022 in different scientific databases, including PubMed Central, Springer, Elsevier, Multidisciplinary Digital Publishing Institute (MDPI), IEEE Xplore, and Frontiers. It results in the quantitative and qualitative analysis of 103 scientific papers. The study demonstrated that different datasets are available online with data related to various diseases. Several ML/DP-based models were identified in the research, where Convolutional Neural Network and Support Vector Machine were the most applied algorithms. This review can allow us to identify the techniques that can be used in a system that promotes the patient's autonomy.

Artificial Intelligence in Hepatology- Ready for the Primetime.

Artificial Intelligence (AI) is a mathematical process of computer mediating designing of algorithms to support human intelligence. AI in hepatology has shown tremendous promise to plan appropriate management and hence improve treatment outcomes. The field of AI is in a very early phase with limited clinical use. AI tools such as machine learning, deep learning, and 'big data' are in a continuous phase of evolution, presently being applied for clinical and basic research. In this review, we have summarized various AI applications in hepatology, the pitfalls and AI's future implications. Different AI models and algorithms are under study using clinical, laboratory, endoscopic and imaging parameters to diagnose and manage liver diseases and mass lesions. AI has helped to reduce human errors and improve treatment protocols. Further research and validation are required for future use of AI in hepatology.

Repurposing of drugs for combined treatment of COVID-19 cytokine storm using machine learning.

Severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) induced cytokine storm is the major cause of COVID-19 related deaths. Patients have been treated with drugs that work by inhibiting a specific protein partly responsible for the cytokines production. This approach provided very limited success, since there are multiple proteins involved in the complex cell signaling disease mechanisms. We targeted five proteins: Angiotensin II receptor type 1 (AT1R), A disintegrin and metalloprotease 17 (ADAM17), Nuclear Factor­Kappa B (NF­κB), Janus kinase 1 (JAK1) and Signal Transducer and Activator of Transcription 3 (STAT3), which are involved in the SARS­CoV­2 induced cytokine storm pathway. We developed machine-learning (ML) models for these five proteins, using known active inhibitors. After developing the model for each of these proteins, FDA-approved drugs were screened to find novel therapeutics for COVID­19. We identified twenty drugs that are active for four proteins with predicted scores greater than 0.8 and eight drugs active for all five proteins with predicted scores over 0.85. Mitomycin C is the most active drug across all five proteins with an average prediction score of 0.886. For further validation of these results, we used the PyRx software to conduct protein-ligand docking experiments and calculated the binding affinity. The docking results support findings by the ML model. This research study predicted that several drugs can target multiple proteins simultaneously in cytokine storm-related pathway. These may be useful drugs to treat patients because these therapies can fight cytokine storm caused by the virus at multiple points of inhibition, leading to synergistically effective treatments.

Computational tools for exploring peptide-membrane interactions in gram-positive bacteria.

The vital cellular functions in Gram-positive bacteria are controlled by signaling molecules known as quorum sensing peptides (QSPs), considered promising therapeutic interventions for bacterial infections. In the bacterial system QSPs bind to membrane-coupled receptors, which then auto-phosphorylate and activate intracellular response regulators. These response regulators induce target gene expression in bacteria. One of the most reliable trends in drug discovery research for virulence-associated molecular targets is the use of peptide drugs or new functionalities. In this perspective, computational methods act as auxiliary aids for biologists, where methodologies based on machine learning and in silico analysis are developed as suitable tools for target peptide identification. Therefore, the development of quick and reliable computational resources to identify or predict these QSPs along with their receptors and inhibitors is receiving considerable attention. The databases such as Quorumpeps and Quorum Sensing of Human Gut Microbes (QSHGM) provide a detailed overview of the structures and functions of QSPs. The tools and algorithms such as QSPpred, QSPred-FL, iQSP, EnsembleQS and PEPred-Suite have been used for the generic prediction of QSPs and feature representation. The availability of compiled key resources for utilizing peptide features based on amino acid composition, positional preferences, and motifs as well as structural and physicochemical properties, including biofilm inhibitory peptides, can aid in elucidating the QSP and membrane receptor interactions in infectious Gram-positive pathogens. Herein, we present a comprehensive survey of diverse computational approaches that are suitable for detecting QSPs and QS interference molecules. This review highlights the utility of these methods for developing potential biomarkers against infectious Gram-positive pathogens.