Machine Learning-Based Drug Repositioning of Novel Janus Kinase 2 Inhibitors Utilizing Molecular Docking and Molecular Dynamic Simulation

Machine learning algorithms have been increasingly applied in drug development due to their efficiency and effectiveness. Machine learning-based drug repurposing can contribute to the identification of novel therapeutic applications for drugs with other indications. The current study used a trained machine learning model to screen a vast chemical library for new JAK2 inhibitors, the biological activities of which were reported. Reference JAK2 inhibitors, comprising 1911 compounds, have experimentally determined IC50 values. To generate the input to the machine learning model, reference compounds were subjected to RDKit, a cheminformatic toolkit, to extract molecular descriptors. A Random Forest Regression model from the Scikit-learn machine learning library was applied to obtain a predictive regression model and to analyze each molecular descriptor’s role in determining IC50 values in the reference data set. Then, IC50 values of the library compounds, comprised of 1,576,903 compounds, were predicted using the generated regression model. Interestingly, some compounds that exhibit high IC50 values from the prediction were reported to possess JAK inhibition activity, which indicates the limitations of the prediction model. To confirm the JAK2 inhibition activity of predicted compounds, molecular docking and molecular dynamics simulation were carried out with the JAK inhibitor reference compound, tofacitinib. The binding affinity of docked compounds in the active region of JAK2 was also analyzed by the gmxMMPBSA approach. Furthermore, experimental validation confirmed the results from the computational analysis. Results showed highly comparable outcomes concerning tofacitinib. Conclusively, the machine learning model can efficiently improve the virtual screening of drugs and drug development

Baseline characteristics of patients with tuberculosis.

<p>IQR, interquartile range; TB, tuberculosis; ICU, intensive care unit; CRP, C-reactive protein.</p><p>^aThe data are presented as medians (IQR) for age, body mass index, and hemoglobin and as n (%) for all other factors.</p><p>Baseline characteristics of patients with tuberculosis.</p

S2 Fig -

BackgroundHyperuricemia is common during tuberculosis (TB) treatment, especially in association with pyrazinamide (PZA). This study investigated the relationship between major adverse cardiovascular events (MACEs) and hyperuricemia during TB treatment.MethodsWe conducted a single-center retrospective cohort study. From January 2010 through June 2017, we assessed all consecutive TB patients at Chonnam National University Hospital in South Korea. Hyperuricemia was defined as serum uric acid levels exceeding 7.0 mg/dL (men) and 6.0 mg/dL (women).ResultsOf the 1,143 patients included, PZA was administered to 1,081 (94.6%), and hyperuricemia was detected in 941 (82.3%). Eight patients experienced MACEs. Multivariate analysis using logistic regression indicated that prior ischemic heart disease was associated with MACE development (OR,14.087; 95% CI,3.304–60.061; P ConclusionsAlthough most patients treated with PZA developed hyperuricemia, it was not associated with MACE development. Hyperuricemia during TB treatment was associated with better outcomes, possibly due to consistent adherence to TB treatment.</div

Patient inclusion and exclusion flow chart.

Out of the 1,674 tuberculosis patients treated at our hospital, 531 were excluded, leading to a final count of 1,143 patients in this study.</p

Eriocaulon sexangulare L.

原著和名: オホシラタマホシクサ科名: ホシクサ科 = Eriocaulaceae採集地: 沖縄県 西表島 カンピラ滝 (琉球 西表島 カンピラ滝)採集日: 1986/12/9採集者: 萩庭丈壽整理番号: JH006192国立科学博物館整理番号: TNS-VS-95619

S1 Dataset -

BackgroundHyperuricemia is common during tuberculosis (TB) treatment, especially in association with pyrazinamide (PZA). This study investigated the relationship between major adverse cardiovascular events (MACEs) and hyperuricemia during TB treatment.MethodsWe conducted a single-center retrospective cohort study. From January 2010 through June 2017, we assessed all consecutive TB patients at Chonnam National University Hospital in South Korea. Hyperuricemia was defined as serum uric acid levels exceeding 7.0 mg/dL (men) and 6.0 mg/dL (women).ResultsOf the 1,143 patients included, PZA was administered to 1,081 (94.6%), and hyperuricemia was detected in 941 (82.3%). Eight patients experienced MACEs. Multivariate analysis using logistic regression indicated that prior ischemic heart disease was associated with MACE development (OR,14.087; 95% CI,3.304–60.061; P ConclusionsAlthough most patients treated with PZA developed hyperuricemia, it was not associated with MACE development. Hyperuricemia during TB treatment was associated with better outcomes, possibly due to consistent adherence to TB treatment.</div

Comparison of microbiological characteristics between community- and hospital-acquired pleural infections.

Comparison of microbiological characteristics between community- and hospital-acquired pleural infections.</p

Risk factors associated with death during tuberculosis treatment.

Risk factors associated with death during tuberculosis treatment.</p

Comparisons between patients with and without major adverse cardiac events.

Comparisons between patients with and without major adverse cardiac events.</p