Feature Engineering-Assisted Drug Repurposing on Disease-Drug Transcriptome Profiles in Gastric Cancer.

Gastric cancer is one of the most common and deadly types of cancer in the world. To develop new biomarkers and drugs to diagnose and treat this cancer, it is necessary to identify the differences between the transcriptome profiles of gastric cancer and healthy individuals, identify critical genes associated with these differences, and make potential drug predictions based on these genes. In this study, using two gene expression datasets related to gastric cancer (GSE19826 and GSE79973), 200 genes that were ready for machine learning were selected, and their expression levels were analyzed. The best 100 genes for the model were chosen with the permutation feature importance method, and central genes, such as SCARB1, ETV3, SPATA17, FAM167A-AS1, and MTBP, which were shown to be associated with gastric cancer, were identified. Then, using the drug repurposing method with the Connectivity Map CLUE Query tools, potential drugs such as Forskolin, Gestrinone, Cediranib, Apicidine, and Everolimus, which showed a highly negative correlation with the expression levels of the selected genes, were identified. This study provides a method to develop new approaches to diagnosing and treating gastric cancer by comparing the transcriptome profiles of patients gastric cancer and performing a feature engineering-assisted drug repurposing analysis based on cancer data.

Explainable artificial intelligence in the design of selective carbonic anhydrase I-II inhibitors via molecular fingerprinting.

Inhibiting the enzymes carbonic anhydrase I (CA I) and carbonic anhydrase II (CA II) presents a potential avenue for addressing nervous system ailments such as glaucoma and Alzheimer's disease. Our study explored harnessing explainable artificial intelligence (XAI) to unveil the molecular traits inherent in CA I and CA II inhibitors. The PubChem molecular fingerprints of these inhibitors, sourced from the ChEMBL database, were subjected to detailed XAI analysis. The study encompassed training 10 regression models using IC50 values, and their efficacy was gauged using metrics including R2, RMSE, and time taken. The Decision Tree Regressor algorithm emerged as the optimal performer (R2: 0.93, RMSE: 0.43, time-taken: 0.07). Furthermore, the PFI method unveiled key molecular features for CA I inhibitors, notably PubChemFP432 (C(O)N) and PubChemFP6978 (C(O)O). The SHAP analysis highlighted the significance of attributes like PubChemFP539 (C(O)NCC), PubChemFP601 (C(O)OCC), and PubChemFP432 (C(O)N) in CA I inhibitiotable n. Likewise, features for CA II inhibitors encompassed PubChemFP528(C(O)OCCN), PubChemFP791 (C(O)OCCC), PubChemFP696 (C(O)OCCCC), PubChemFP335 (C(O)NCCN), PubChemFP580 (C(O)NCCCN), and PubChemFP180 (C(O)NCCC), identified through SHAP analysis. The sulfonamide group (S), aromatic ring (A), and hydrogen bonding group (H) exert a substantial impact on CA I and CA II enzyme activities and IC50 values through the XAI approach. These insights into the CA I and CA II inhibitors are poised to guide future drug discovery efforts, serving as a beacon for innovative therapeutic interventions.

Targeting Breast Cancer with N-Acetyl-D-Glucosamine: Integrating Machine Learning and Cellular Assays for Promising Results.

BACKGROUND: Breast cancer is a common cancer with high mortality rates. Early diagnosis is crucial for reducing the prognosis and mortality rates. Therefore, the development of alternative treatment options is necessary. OBJECTIVE: This study aimed to investigate the inhibitory effect of N-acetyl-D-glucosamine (D-GlcNAc) on breast cancer using a machine learning method. The findings were further confirmed through assays on breast cancer cell lines. METHODS: MCF-7 and 4T1 cell lines (ATCC) were cultured in the presence and absence of varying concentrations of D-GlcNAc (0.5 mM, 1 mM, 2 mM, and 4 mM) for 72 hours. A xenograft mouse model for breast cancer was established by injecting 4T1 cells into mammary glands. D-GlcNAc (2 mM) was administered intraperitoneally to mice daily for 28 days, and histopathological effects were evaluated at pre-tumoral and post-tumoral stages. RESULTS: Treatment with 2 mM and 4 mM D-GlcNAc significantly decreased cell proliferation rates in MCF-7 and 4T1 cell lines and increased Fas expression. The number of apoptotic cells was significantly higher than untreated cell cultures (p < 0.01 - p < 0.0001). D-GlcNAc administration also considerably reduced tumour size, mitosis, and angiogenesis in the post-treatment group compared to the control breast cancer group (p < 0.01 - p < 0.0001). Additionally, molecular docking/dynamic analysis revealed a high binding affinity of D-GlcNAc to the marker protein HER2, which is involved in tumour progression and cell signalling. CONCLUSION: Our study demonstrated the positive effect of D-GlcNAc administration on breast cancer cells, leading to increased apoptosis and Fas expression in the malignant phenotype. The binding affinity of D-GlcNAc to HER2 suggests a potential mechanism of action. These findings contribute to understanding D-GlcNAc as a potential anti-tumour agent for breast cancer treatment.

Explainable artificial intelligence-assisted virtual screening and bioinformatics approaches for effective bioactivity prediction of phenolic cyclooxygenase-2 (COX-2) inhibitors using PubChem molecular fingerprints.

Cyclooxygenase-2 (COX-2) inhibitors are nonsteroidal anti-inflammatory drugs that treat inflammation, pain and fever. This study determined the interaction mechanisms of COX-2 inhibitors and the molecular properties needed to design new drug candidates. Using machine learning and explainable AI methods, the inhibition activity of 1488 molecules was modelled, and essential properties were identified. These properties included aromatic rings, nitrogen-containing functional groups and aliphatic hydrocarbons. They affected the water solubility, hydrophobicity and binding affinity of COX-2 inhibitors. The binding mode, stability and ADME properties of 16 ligands bound to the Cyclooxygenase active site of COX-2 were investigated by molecular docking, molecular dynamics simulation and MM-GBSA analysis. The results showed that ligand 339,222 was the most stable and effective COX-2 inhibitor. It inhibited prostaglandin synthesis by disrupting the protein conformation of COX-2. It had good ADME properties and high clinical potential. This study demonstrated the potential of machine learning and bioinformatics methods in discovering COX-2 inhibitors.

Identifying Cardiovascular Disease Risk Factors in Adults with Explainable Artificial Intelligence.

BACKGROUND: The aim of this study was to evaluate the relationship between risk factors causing cardiovascular diseases and their importance with explainable machine learning models. METHODS: In this retrospective study, multiple databases were searched, and data on 11 risk factors of 70 000 patients were obtained. Data included risk factors highly associated with cardiovascular disease and having/not having any cardiovascular disease. The explainable prediction model was constructed using 7 machine learning algorithms: Random Forest Classifier, Extreme Gradient Boost Classifier, Decision Tree Classifier, KNeighbors Classifier, Support Vector Machine Classifier, and GaussianNB. Receiver operating characteristic curve, Brier scores, and mean accuracy were used to assess the model's performance. The interpretability of the predicted results was examined using Shapley additive description values. RESULTS: The accuracy, area under the curve values, and Brier scores of the Extreme Gradient Boost model (the best prediction model for cardiovascular disease risk factors) were calculated as 0.739, 0.803, and 0.260, respectively. The most important risk factors in the permutation feature importance method and explainable artificial intelligence-Shapley's explanations method are systolic blood pressure (ap_hi) [0.1335 ± 0.0045 w (weight)], cholesterol (0.0341 ± 0.0022 w), and age (0.0211 ± 0.0036 w). CONCLUSION: The created explainable machine learning model has become a successful clinical model that can predict cardiovascular patients and explain the impact of risk factors. Especially in the clinical setting, this model, which has an accurate, explainable, and transparent algorithm, will help encourage early diagnosis of patients with cardiovascular diseases, risk factors, and possible treatment options.

Data mining and molecular dynamics analysis to detect HIV-1 reverse transcriptase RNase H activity inhibitor.

HIV-1 is a deadly virus that affects millions of people worldwide. In this study, we aimed to inhibit viral replication by targeting one of the HIV-1 proteins and identifying a new drug candidate. We used data mining and molecular dynamics methods on HIV-1 genomes. Based on MAUVE analysis, we selected the RNase H activity of the reverse transcriptase (R.T) enzyme as a potential target due to its low mutation rate and high conservation level. We screened about 94,000 small molecule inhibitors by virtual screening. We validated the hit compounds' stability and binding free energy through molecular dynamics simulations and MM/PBSA. Phomoarcherin B, known for its anticancer properties, emerged as the best candidate and showed potential as an HIV-1 reverse transcriptase RNase H activity inhibitor. This study presents a new target and drug candidate for HIV-1 treatment. However, in vitro and in vivo tests are required. Also, the effect of RNase H activity on viral replication and the interaction of Phomoarcherin B with other HIV-1 proteins should be investigated.

Explainability and white box in drug discovery.

Recently, artificial intelligence (AI) techniques have been increasingly used to overcome the challenges in drug discovery. Although traditional AI techniques generally have high accuracy rates, there may be difficulties in explaining the decision process and patterns. This can create difficulties in understanding and making sense of the outputs of algorithms used in drug discovery. Therefore, using explainable AI (XAI) techniques, the causes and consequences of the decision process are better understood. This can help further improve the drug discovery process and make the right decisions. To address this issue, Explainable Artificial Intelligence (XAI) emerged as a process and method that securely captures the results and outputs of machine learning (ML) and deep learning (DL) algorithms. Using techniques such as SHAP (SHApley Additive ExPlanations) and LIME (Locally Interpretable Model-Independent Explanations) has made the drug targeting phase clearer and more understandable. XAI methods are expected to reduce time and cost in future computational drug discovery studies. This review provides a comprehensive overview of XAI-based drug discovery and development prediction. XAI mechanisms to increase confidence in AI and modeling methods. The limitations and future directions of XAI in drug discovery are also discussed.

CVD22: Explainable artificial intelligence determination of the relationship of troponin to D-Dimer, mortality, and CK-MB in COVID-19 patients.

BACKGROUND AND PURPOSE: COVID-19, which emerged in Wuhan (China), is one of the deadliest and fastest-spreading pandemics as of the end of 2019. According to the World Health Organization (WHO), there are more than 100 million infectious cases worldwide. Therefore, research models are crucial for managing the pandemic scenario. However, because the behavior of this epidemic is so complex and difficult to understand, an effective model must not only produce accurate predictive results but must also have a clear explanation that enables human experts to act proactively. For this reason, an innovative study has been planned to diagnose Troponin levels in the COVID-19 process with explainable white box algorithms to reach a clear explanation. METHODS: Using the pandemic data provided by Erzurum Training and Research Hospital (decision number: 2022/13-145), an interpretable explanation of Troponin data was provided in the COVID-19 process with SHApley Additive exPlanations (SHAP) algorithms. Five machine learning (ML) algorithms were developed. Model performances were determined based on training, test accuracies, precision, F1-score, recall, and AUC (Area Under the Curve) values. Feature importance was estimated according to Shapley values by applying the SHApley Additive exPlanations (SHAP) method to the model with high accuracy. The model created with Streamlit v.3.9 was integrated into the interface with the name CVD22. RESULTS: Among the five-machine learning (ML) models created with pandemic data, the best model was selected with the values of 1.0, 0.83, 0.86, 0.83, 0.80, and 0.91 in train and test accuracy, precision, F1-score, recall, and AUC values, respectively. As a result of feature selection and SHApley Additive exPlanations (SHAP) algorithms applied to the XGBoost model, it was determined that DDimer mean, mortality, CKMB (creatine kinase myocardial band), and Glucose were the features with the highest importance over the model estimation. CONCLUSIONS: Recent advances in new explainable artificial intelligence (XAI) models have successfully made it possible to predict the future using large historical datasets. Therefore, throughout the ongoing pandemic, CVD22 (https://cvd22covid.streamlitapp.com/) can be used as a guide to help authorities or medical professionals make the best decisions quickly.

Development of gold nanoparticle-based biosensors for COVID-19 diagnosis.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative organism of coronavirus disease 2019 (COVID-19) which poses a significant threat to public health worldwide. Though there are certain recommended drugs that can cure COVID-19, their therapeutic efficacy is limited. Therefore, the early and rapid detection without compromising the test accuracy is necessary in order to provide an appropriate treatment for the disease suppression. Main body: Nanoparticles (NPs) can closely mimic the virus and interact strongly with its proteins due to their morphological similarities. NPs have been widely applied in a variety of medical applications, including biosensing, drug delivery, antimicrobial treatment, and imaging. Recently, NPs-based biosensors have attracted great interest for their biological activities and specific sensing properties, which allows the detection of analytes such as nucleic acids (DNA or RNA), aptamers, and proteins in clinical samples. Further, the advances of nanotechnologies have enabled the development of miniaturized detection systems for point-of-care biosensors, a new strategy for detecting human viral diseases. Among the various NPs, the specific physicochemical properties of gold NPs (AuNPs) are being widely used in the field of clinical diagnostics. As a result, several AuNP-based colorimetric detection methods have been developed. Short conclusion: The purpose of this review is to provide an overview of the development of AuNPs-based biosensors by virtue of its powerful characteristics as a signal amplifier or enhancer that target pathogenic RNA viruses that provide a reliable and effective strategy for detecting of the existing or newly emerging SARS-CoV-2.

Decellularized Alstroemeria flower stem modified with chitosan for tissue engineering purposes: A cellulose/chitosan scaffold.

Utilizing plant-based scaffolds has pulled in the consideration of tissue engineers. Plant tissues own different structures with particular porosity and structure. In this study, the stem of the Alstroemeria flower was designated for decellularization to fabricate a new scaffold. The stems were decellularized and called AFSP and then modified by chitosan and named AFSPC. Osteoblast precursor cell line was employed to assess the biological potential of the final scaffolds. The results uncovered that AFSP owns linear microchannels with a smooth surface. AFSPC delineated uniform chitosan coating on the walls with appropriate roughness. AFSPC showed higher potential in swelling, degradation, diffusion, and having a porous structure than AFSP. Modification with chitosan improved mechanical behavior. Biological assays depicted no cytotoxicity for AFSP and AFSPC. AFSPC showed good cell attachment, proliferation, and migration. In conclusion, modified tissue plants can be a good candidate for tissue engineering of both soft and hard tissues.