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discovery of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (dYRK1A) inhibitors using an artificial intelligence model and their effects on tau and tubulin dynamics

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Biomedicine and pharmacotherapy 2024年 181卷 117688-117688页

作者： Chen, Jun-Hong Tu, Huang-Ju Lin, Tony Eight Peng, Zhao-Xiang Wu, Yi-Wen Yen, Shih-Chung Sung, Tzu-Ying Hsieh, Jui-Hua Lee, Hsueh-Yun Pan, Shiow-Lin HuangFu, Wei-Chun Hsu, Kai-Cheng Graduate Institute of Cancer Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei Taiwan Ph.D. Program for Cancer Molecular Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei Taiwan Warshel Institute for Computational Biology The Chinese University of Hong Kong Guangdong Shenzhen China Division of Translational Toxicology National Institute of Environmental Health Sciences National Institutes of Health Durham NC United States School of Pharmacy College of Pharmacy Taipei Medical University Taipei Taiwan TMU Research Center of Cancer Translational Medicine Taipei Medical University Taipei Taiwan Cancer Center Wan Fang Hospital Taipei Medical University Taipei Taiwan

The dual-specificity tyrosine-phosphorylation-regulated kinase 1 A (dYRK1A) presents a promising therapeutic target for neurological diseases. However, current inhibitors lack selectivity, which can lead to unexpected side effects and increase the difficulty of studying dYRK1A. Therefore, identifying selective inhibitors targeting dYRK1A is essential for reducing side effects and facilitating neurological disease research. This study aimed to discover dYRK1A inhibitors through a screening pipeline incorporating a deep neural network (dNN) model. Herein, we report an optimized model with an accuracy of 0.93 on a testing set. The pipeline was then performed to identify potential dYRK1A inhibitors from the National Cancer Institute (NCI) library. Four novel dYRK1A inhibitors were identified, and compounds NSC657702 and NSC31059 were noteworthy for their potent inhibition, with IC₅₀ values of 50.9 and 39.5 nM, respectively. NSC31059 exhibited exceptional selectivity across 70 kinases. The compounds also significantly reduced dYRK1A-induced tau phosphorylation at key sites associated with the pathology of neurodegenerative diseases. Moreover, they promoted tubulin polymerization, suggesting a role in microtubule stabilization. Cytotoxicity assessments further confirmed the neuronal safety of the compounds. Together, the results demonstrated a promising screening pipeline and novel dYRK1A inhibitors as candidates for further optimization and development. © 2024 The Authors

关键词： deep Learning dYRK1A Tau

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Applications of engineered biochar in remediation of heavy metal(loid)s pollution from wastewater: Current perspectives toward sustainable development goals

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science of the Total Environment 2024年 926卷 171859页

作者： Tran, Thien-Khanh Huynh, Loan Nguyen, Hoang-Lam Nguyen, Minh-Ky Lin, Chitsan Hoang, Tuan-dung Hung, Nguyen Tri Q. Nguyen, X. Hoan Chang, S. Woong Nguyen, d. duc Advanced Applied Sciences Research Group Dong Nai Technology University Bien Hoa City76100 Viet Nam Faculty of Technology Dong Nai Technology University Bien Hoa City76100 Viet Nam Department of Civil Engineering McGill University Montreal Canada Faculty of Environment and Natural Resources Nong Lam University Hamlet 6 Linh Trung Ward Thu Duc City Ho Chi Minh City700000 Viet Nam Ph.D. Program in Maritime Science and Technology National Kaohsiung University of Science and Technology Kaohsiung81157 Taiwan Department of Marine Environmental Engineering National Kaohsiung University of Science and Technology Kaohsiung81157 Taiwan School of Chemistry and Life Science Hanoi University of Science and Technology No. 1 Dai Co Viet Hai Ba Trung Hanoi100000 Viet Nam Vietnam National University Hanoi - School of Interdisciplinary Sciences and Arts 144 Xuan Thuy Street Cau Giay District Hanoi100000 Viet Nam Ho Chi Minh City University of Industry and Trade Ho Chi Minh City Viet Nam Department of Civil & Energy System Engineering Kyonggi University Suwon16227 Korea Republic of Institute of Applied Technology and Sustainable Development Nguyen Tat Thanh University Ho Chi Minh City700000 Viet Nam

environmental pollution of heavy metal(loid)s (HMs) caused adverse impacts, has become one of the emerging concerns and challenges worldwide. Metal(loid)s can pose significant threats to living organisms even when present in trace levels within environmental matrices. Extended exposure to these substances can lead to adverse health consequences in humans. Removing HM-contaminated water and moving toward sustainable development goals (SdGs) is critical. In this mission, biochar has recently gained attention in the environmental sector as a green and alternative material for wastewater removal. This work provides a comprehensive analysis of the remediation of typical HMs by biochars, associated with an understanding of remediation mechanisms, and gives practical solutions for ecologically sustainable. Applying engineered biochar in various fields, especially with nanoscale biochar-aided wastewater treatment approaches, can eliminate hazardous metal(loid) contaminants, highlighting an environmentally friendly and low-cost method. Surface modification of engineered biochar with nanomaterials is a potential strategy that positively influences its sorption capacity to remove contaminants. The research findings highlighted the biochars' ability to adsorb HM ions based on increased specific surface area (SSA), heightened porosity, and forming inner-sphere complexes with oxygen-rich groups. Utilizing biochar modification emerged as a viable approach for addressing lead (Pb), cadmium (Cd), arsenic (As), mercury (Hg), and chromium (Cr) pollution in aqueous environments. Most biochars investigated demonstrated a removal efficiency >90 % (Cd, As, Hg) and can reach an impressive 99 % (Pb and Cr). Furthermore, biochar and advanced engineered applications are also considered alternative solutions based on the circular economy. © 2024 Elsevier B.V.

关键词： Nanostructured materials

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Electrochemical biosensor based on an atomic layered composite of graphene oxide/graphene as an electrode material towards selective and sensitive detection of miRNA-21

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Microchemical Journal 2024年 199卷

作者： Huang, Min-Shin Govindasamy, Mani Chinnapaiyan, Sathishkumar Lin, Yi-Ting Lu, Shao-Yang Samukawa, Seiji Huang, Chi-Hsien Department of Materials Engineering Ming Chi University of Technology New Taipei City 243303 Taiwan International Ph.D. Program in Innovative Technology of Biomedical Engineering and Medical Devices Ming Chi University of Technology New Taipei City 24303 Taiwan Centre for Applied Research Saveetha School of Engineering Saveetha Institute of Medical and Technical Sciences (SIMATS) Chennai-602105 Tamil Nadu India Institute of Fluid Science Tohoku University Sendai 980-8577 Japan College of Electrical and Computer Engineering National Yang Ming Chiao Tung University Hsinchu 300093 Taiwan Division of Rheumatology Allergy and Immunology Chang Gung Memorial Hospital Taoyuan City 33305 Taiwan College of Engineering Chang Gung University Taoyuan City 33302 Taiwan

development of an efficient technique towards the detection of miRNAs is highly significant for the timely diagnosis and prognosis of cancers. In this study, we utilized the chemical vapor deposition (CVd) technique to grow bilayer graphene (BLG) on copper foil and subsequently transferred the BLG to fluorine doped tin oxide (FTO) substrate via a facile wet transfer technique. The upper layer of the BLG was modified to graphene oxide (GO) with a low damage plasma treatment (LdPT) process to serve as a biomolecule receiving layer and the lower graphene layer (G) serves as an electron transport layer. The developed GO/G/FTO platform offers superior sensing ability towards the miRNA-21. The results demonstrated that the proposed GO/G/FTO substrate detect the miRNA-21 with a wide linear range (10 fM ∼ 1 nM), low limit of detection (3.18 fM), high sensitivity (0.6 mApM⁻¹cm⁻²), selectivity and stability via the differential pulse voltammetry method. Additionally, the sensors can efficiently discriminate the target miRNA-21 from its complementary base mismatched counterparts. The proposed approach serves as an excellent tool for the early diagnosis of diseases. © 2024 Elsevier B.V.

关键词： Atomic layer oxidation Biosensor Cancer biomarkers Electrochemical Graphene oxide Plasma treatment

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Ultrasensitive detection of ornidazole–antibiotic drug residues in water using NiMOFs functionalized MWCNT modified electrode

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Microchemical Journal 2024年 197卷

作者： Vignesh, Kondusamy Senthil Kumar, Annamalai Arumugam Napoleon, Ayyakannu Kuo, Chih-Yu Yusuf, Kareem Govindasamy, Mani Nano and Bioelectrochemistry Research Laboratory Carbon dioxide Research and Green Technology Centre and Department of Chemistry School of Advanced Sciences Vellore Institute of Technology Vellore 632 014 India Department of Chemistry School of Advanced Sciences Vellore Institute of Technology Vellore 632 014 India International Ph.D. Program in Innovative Technology of Biomedical Engineering and Medical Devices Ming Chi University of Technology New Taipei City 243303 Taiwan Department of Chemical Engineering and Biotechnology National Taipei University of Technology Taipei 10608 Taiwan Department of Chemistry College of Science King Saud University Riyadh 11451 Saudi Arabia Centre for Applied Research Saveetha School of Engineering Saveetha Institute of Medical and Technical Sciences (SIMATS) Tamil Nadu Chennai 602105 India Research Center for Intelligence Medical Devices Ming Chi University of Technology New Taipei City 243303 Taiwan

Nitroimidazole-based drugs are widely used as an antibiotic for the treatment of anaerobic bacterial and parasite illnesses. The widespread use of these drugs in animal feed and the consequent environmental pollution have become significant concerns in recent years. Simple, sensitive, and rapid detection of the antibody in various real samples is demanding research interest. Herein, we report a Nickel-metal organic framework functionalized Multiwalled Carbon nanotubes modified glassy carbon electrode (MWCNT@NiMOFs) as an ultrasensitive and rapid voltammetric sensor for the detection of ornidazole (ORdZ) in a neutral ph solution. The MWCNT@NiMOFs were prepared using a microwave-assisted solvothermal technique accompanied by an ultrasonication method. The designed MWCNT@NiMOFs offered a low charge transfer resistance (R_ct) of 141 Ω along with excellent electrocatalytic activity, and high current density at the lowered cathodic peak potential (-0.62 V vs Ag/AgCl) for ORdZ detection. The surface adsorption capacity (Γ_s) in terms of surface excess and heterogeneous charge transfer rate constant (k⁰) of the MWCNT@NiMOFs were calculated to be 3.29 × 10^-9 mol cm⁻² and 5.33 × 10^-3 cm s⁻¹, respectively. Under an optimal working condition, differential pulse voltammetry measurements of ORdZ have shown concentration linearity in a window, 100 nm to 10 µM range with excellent sensitivity, 5.69 × 10^-5A µM⁻¹ cm⁻², and detection limit, 26 nM (3.3/s). The designed MWCNT@NiMOFs offered appreciable reproducibility, and repeatability up to 30 days of storage time. The real-time quantitative evaluation of ORdZ in human urine and tap water specimens was done along with ∼ 100 % recovery values. Since the new approach is simple, selective, and separation-free, it can be extendable to a variety of real-time practical applications. © 2024 Elsevier B.V.

关键词： Electrocatalytic reduction Multi-walled carbon nanotubes Nickel Metal-organic frameworks Ornidazole drug Ultrasensitive detection

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Electrochemical sensor based on ZnO@MWCNT/ glassy carbon electrode for the detection of warfarin (blood anticoagulant)

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Surfaces and Interfaces 2025年 67卷

作者： Manjunath, Kumbar Mudakappa Yemmi, Rajeshwari Swamy, B.E. Kumara Eldesoky, Gaber E. Govindasamy, Mani Division of Plant Breeding and Genetics Central Coffee Research Institute Karnataka Chikkamagaluru 577117 India Department of Industrial Chemistry Kuvempu University Karnataka Shivamogga India Department of Chemistry College of Science King Saud University P. O. Box 2455 Riyadh 11451 Saudi Arabia International Ph.D. Program in Innovative Technology of Biomedical Engineering and Medical Devices Ming Chi University of Technology New Taipei City 243303 Taiwan Centre for Applied Research Saveetha School of Engineering Saveetha Institute of Medical and Technical Sciences (SIMATS) Tamil Nadu Chennai 602105 India Research Center for Intelligence Medical Devices Ming Chi University of Technology New Taipei City 243303 Taiwan Department of Chemistry Korea University Seoul Seongbuk-gu South Korea

This study employed ZnO nanoparticles, multi-walled carbon nanotubes (MWCNTs), and a modified glassy carbon electrode (GCE) as a quick and sensitive method for detecting warfarin at biological ph levels. The ultrasonication technique was utilized in the synthesis of the ZnO@MWCNTs nanocomposite. The ZnO@MWCNTs were characterized using Transmission electron microscopy (TEM), Scanning electron microscopy (SEM), X-ray diffraction (XRd), spectroscopy, analytical techniques, and electrochemical impedance spectroscopy (EIS). Cyclic voltammetry (CV) as well as differential pulse voltammetry (dPV) techniques are employed in the presence of PBS buffer as an electrolyte. We observed unique oxidative peak currents an indication of the electrochemical mechanism of warfarin at low potentials for ZnO @MWCNTs/GCE. Moreover, we successfully attained effective electrochemical detection of warfarin utilizing the proposed sensor, which exhibited an excellent low limit of detection (LOd) of 0.0188 μM across a linear range of 0.02–2867.37 μM. The proposed sensor exhibits excellent storage stability, repeatability, and reproducibility, and has been effectively utilized for the quantification of warfarin in real samples, including blood serum and urine as obtained good recovery and RSd value. © 2025 Elsevier B.V.

关键词： differential pulse voltammetry Glassy carbon electrode Multiwalled carbon nanotubes Warfarin ZnO nanoparticles

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environmental determinants of household microbial and allergen levels in the Greater Taipei Area

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Building and Environment 2023年 230卷

作者： phiri, Yohane V.A. Wu, Meei-Maan Chen, Yi-Hua Zou, Ming-Lun Jiang, Chuen-Bin Wu, Chih-da Huang, Hsiao-Chun Lung, Shih-Chun Candice Chien, Ling-Chu Lo, Yu-Chun Lee, Fang-Yu Chao, Hsing Jasmine School of Public Health College of Public Health Taipei Medical University Taipei Taiwan Department of Public Health School of Medicine College of Medicine Taipei Medical University Taipei Taiwan Neuroscience Research Center Taipei Medical University Taipei Taiwan Department of Pediatric Gastroenterology Hepatology and Nutrition MacKay Children's Hospital Taipei Taiwan Department of Medicine MacKay Medical College New Taipei City Taiwan Department of Geomatics National Cheng Kung University Tainan Taiwan National Institute of Environmental Health Sciences National Health Research Institute Miaoli Taiwan Research Center for Environmental Changes Academia Sinica Taipei Taiwan Ph.D. Program for Neural Regenerative Medicine College of Medical Science and Technology Taipei Medical University Taipei Taiwan

People spend most of their time indoors, where they may be exposed to various microorganisms and allergens. In this cross-sectional study, we investigated the relationship between indoor microbial and allergen levels and indoor and outdoor household environmental characteristics. Participants were recruited from an ongoing cohort study in the Greater Taipei Area. Questionnaire administration and environmental sampling were conducted during home visits. Samples were collected from children's bedrooms, living rooms, kitchens, and outdoor areas (balconies) and analyzed for fungal spores, house dust mite allergens (der p 1 and der f 1), endotoxin, and cockroach allergens (Bla g 1). Indoor temperature and relative humidity were also measured, and the land-use characteristics and points of interest surrounding the residences were evaluated within specified radii. The mean levels of outdoor air pollutants were then estimated, and multiple regression analysis was performed to investigate the predictors of indoor microbial and allergen levels. In total, 136 homes were analyzed. The results indicated that dog ownership, air purifier use, and floor cleaning frequency were major predictors of indoor microbial and allergen levels. Moreover, proximity to parks, roads, and forests was associated with elevated levels of indoor microorganisms and allergens. Our results demonstrated that indoor concentrations of certain microorganisms and allergens tended to increase in households located within neighborhoods with particular characteristics. Overall, our research findings contribute to housing intervention protocols and policies aimed at reducing exposure to indoor microorganisms and allergens. Future studies should longitudinally investigate the health effects of indoor microorganisms and allergens. © 2023 Elsevier Ltd

关键词： Forestry

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dual-Targeting EGCG/NO-Supplying protein assembled nanoparticles with Multi-Synergistic effects against atherosclerosis

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Chemical Engineering Journal 2024年 493卷

作者： Lin, Chi Cheng, Tsai-Mu Liu, Yun-Chun Hsu, Fang-Yu Shih, Chun-Ming Tsai, Min-Lang Shih, Chun-Che Mi, Fwu-Long Graduate Institute of Medical Sciences College of Medicine Taipei Medical University Taipei11031 Taiwan The PhD Program for Translational Medicine College of Medical Science and Technology Taipei Medical University Taipei11031 Taiwan Taipei Heart Institute Taipei Medical University Taipei11031 Taiwan Department of Food Science National Taiwan Ocean University Keelung20224 Taiwan Department of Biochemistry and Molecular Cell Biology School of Medicine College of Medicine Taipei Medical University Taipei11031 Taiwan Division of Cardiology and Cardiovascular Research Center Taipei Medical University Hospital Taipei11031 Taiwan Division of Cardiovascular Surgery Department of Surgery Wan Fang Hospital Taipei Medical University Taipei11031 Taiwan Institute of Clinical Medicine School of Medicine National Yang-Ming Chiao Tung University Taipei Taiwan Department of Surgery School of Medicine College of Medicine Taipei Medical University Taipei11031 Taiwan Graduate Institute of Nanomedicine and Medical Engineering College of Biomedical Engineering Taipei Medical University Taipei11031 Taiwan International Ph.D. Program for Cell Therapy and Regeneration Medicine College of Medicine Taipei Medical University Taipei Taiwan

Limited therapeutic options are available to effectively preventing atherosclerosis. Inflammatory endothelial cells, foamy macrophages, and high protease levels contribute to atherosclerotic plaque formation. Studies have shown that catechins effectively scavenge reactive oxygen species (ROS), inhibit monocyte adhesion and reduce cholesterol levels, while nitric oxide (NO) enhances endothelial function. However, due to the poor stability and bioavailability of catechins and the toxicity from the burst release of current synthetic small molecules NO donor, effective delivery of these bioactive compounds to treat atherosclerosis is still a challenge. Herein, a catechin/protein-based NO donor co-delivery nanosystem was designed for combinatorial anti-atherosclerotic therapy. We engineered a (−)-epigallocatechin-3-gallate (EGCG)/NO-releasing protein co-assembled nanocomplex based on specific catechin-protein interactions. Furthermore, the nanocomplex was surface modified with fucoidan (Fu), a sulfated polysaccharide with anti-inflammatory activity. This nanocomplex exhibits sensitivity to ROS, ph, and enzymes. The Fu-functionalized nanoparticles specifically accumulates in atherosclerotic plaques mediated by P-selectin on inflamed endothelial cells and scavenger receptor A (SR-A) on foamy macrophages. Under environmental stimuli that simulate the condition of plaque, the nanoparticles are readily activated to release EGCG and NO in response to excess ROS and high protease levels, exerting the multi-synergistic anti-atherosclerosic effects on reducing monocyte adhesion, promoting NO production to proliferate endothelial cells, lowering ROS levels, and decreasing the foam cell formation in vitro, and reducing lipid accumulation, plaque size, and inflammatory cytokines release in high-fat diet-induced atherosclerosis model in ApoE−/− mice. The integration of plaques targeting ability and multiple therapeutic functions can provide an advanced therapeutic strategy for athero

关键词： Nitric oxide

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The role of input imaging combination and AdC threshold on segmentation of acute ischemic stroke lesion using U-Net

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European Radiology 2023年第9期33卷 6157-6167页

作者： Li, Ya-Hui Lin, Shao-Chieh Chung, Hsiao-Wen Chang, Chia-Ching Peng, Hsu-Hsia Huang, Teng-Yi Shen, Wu-Chung Tsai, Chon-Haw Lo, Yu-Chien Lee, Tung-Yang Juan, Cheng-Hsuan Juan, Cheng-En Chang, Hing-Chiu Liu, Yi-Jui Juan, Chun-Jung Graduate Institute of Biomedical Electronics and Bioinformatics National Taiwan University Taipei Taiwan Department of Medical Imaging China Medical University Hsinchu Hospital No. 199 Sec. 1 Xinglong Rd. Zhubei City Hsinchu County 302 Hsinchu Taiwan Ph.D. Program in Electrical and Communication Engineering Feng Chia University Taichung Taiwan Department of Electrical Engineering National Taiwan University Taipei Taiwan Department of Management Science National Yang Ming Chiao Tung University Hsinchu Taiwan Department of Biomedical Engineering and Environmental Sciences National Tsing Hua University Hsinchu Taiwan Department of Electrical Engineering National Taiwan University of Science and Technology Taipei Taiwan Department of Radiology School of Medicine College of Medicine China Medical University Taichung Taiwan Department of Medical Imaging Medical University Hospital Taichung Taiwan Department of Neurology China Medical University Hospital Taichung Taiwan Cheng Ching Hospital Taichung Taiwan Master’s Program of Biomedical Informatics and Biomedical Engineering Feng Chia University Taichung Taiwan Department of Automatic Control Engineering Feng Chia University No. 100 Wenhwa Rd. Seatwen Taichung 40724 Taiwan Department of Biomedical Engineering The Chinese University of Hong Kong ERB1112 11/F William M.W. Mong Engineering Building N.T Shatin Hong Kong Multi-Scale Medical Robotics Center The Chinese University of Hong Kong N.T Shatin Hong Kong Department of Biomedical Engineering National Defense Medical Center Taipei Taiwan Department of Computer Science and Information Engineering National Taiwan University Taipei Taiwan

Background: To evaluate the effect of the weighting of input imaging combo and AdC threshold on the performance of the U-Net and to find an optimized input imaging combo and AdC threshold in segmenting acute ischemic stroke (AIS) lesion. Methods: This study retrospectively enrolled a total of 212 patients having AIS. Four combos, including AdC-AdC-AdC (AAA), dWI-AdC-AdC (dAA), dWI-dWI-AdC (ddA), and dWI-dWI-dWI (ddd), were used as input images, respectively. Three AdC thresholds including 0.6, 0.8 and 1.8 × 10^–3 mm²/s were applied. dice similarity coefficient (dSC) was used to evaluate the segmentation performance of U-Nets. Nonparametric Kruskal–Wallis test with Tukey–Kramer post-hoc tests were used for comparison. A p <.05 was considered statistically significant. Results: The dSC significantly varied among different combos of images and different AdC thresholds. Hybrid U-Nets outperformed uniform U-Nets at AdC thresholds of 0.6 × 10^–3 mm²/s and 0.8 × 10^–3 mm²/s (p <.001). The U-Net with imaging combo of ddd had segmentation performance similar to hybrid U-Nets at an AdC threshold of 1.8 × 10^–3 mm²/s (p =.062 to 1). The U-Net using the imaging combo of dAA at the AdC threshold of 0.6 × 10^–3 mm²/s achieved the highest dSC in the segmentation of AIS lesion. Conclusions: The segmentation performance of U-Net for AIS varies among the input imaging combos and AdC thresholds. The U-Net is optimized by choosing the imaging combo of dAA at an AdC threshold of 0.6 × 10^–3 mm²/s in segmentating AIS lesion with highest dSC. Key Points: • Segmentation performance of U-Net for AIS differs among input imaging combos. • Segmentation performance of U-Net for AIS differs among AdC thresholds. • U-Net is optimized using dAA with AdC = 0.6 × 10^–3mm²/s. © 2023, The Author(s), under exclusive licence to European Society of Radiology.

关键词： deep Learning diffusion Magnetic Resonance Imaging Ischemic Stroke Neural Networks, Computer Retrospective Study

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Corrigendum to "development and functional evaluation of a hyaluronic acid coated nano-formulation with kaempferol as a novel intra-articular agent for knee osteoarthritis treatment"[ Biomed. pharmacother. 175(2024) 116717]

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Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2024年 177卷 116944页

作者： Ching-Yu Lee Yu-Chu Chang Kai-Chiang Yang Yung-Fang Lin Alexander T H Wu Ching-Li Tseng International Ph.D. Program in Cell Therapy and Regenerative Medicine College of Medicine Taipei Medical University Taipei 110301 Taiwan Department of Orthopedics Taipei Medical University Hospital Taipei 110301 Taiwan Department of Orthopaedics School of Medicine College of Medicine Taipei Medical University Taipei 110301 Taiwan Orthopedic Research Center Taipei Medical University Hospital Taipei 110301 Taiwan. Department of Biochemistry and Molecular Cell Biology School of Medicine College of Medicine Taipei Medical University Taipei 110301 Taiwan. School of Dental Technology College of Oral Medicine Taipei Medical University Taipei 110301 Taiwan. Graduate Institute of Biomedical Materials and Tissue Engineering College of Biomedical Engineering Taipei Medical University Taipei 110301 Taiwan International Ph.D. Program in Biomedical Engineering College of Biomedical Engineering Taipei Medical University Taipei 110301 Taiwan. The Ph.D. Program for Translational Medicine College of Medical Science and Technology Taipei Medical University Taipei 110301 Taiwan Clinical Research Center Taipei Medical University Hospital Taipei Medical University Taipei 110301 Taiwan. Electronic address: chaw1211@tmu.edu.tw. International Ph.D. Program in Biomedical Engineering College of Biomedical Engineering Taipei Medical University Taipei 110301 Taiwan. Electronic address: chingli@tmu.edu.tw.

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An ensemble machine learning model generates a focused screening library for the identification of CdK8 inhibitors

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Protein science 2024年第6期33卷 e5007-e5007页

作者： Lin, Tony Eight Yen, dyan HuangFu, Wei-Chun Wu, Yi-Wen Hsu, Jui-Yi Yen, Shih-Chung Sung, Tzu-Ying Hsieh, Jui-Hua Pan, Shiow-Lin Yang, Chia-Ron Huang, Wei-Jan Hsu, Kai-Cheng Graduate Institute of Cancer Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei Taiwan Ph.D. Program for Cancer Molecular Biology and Drug Discovery College of Medical Science and Technology Taipei Medical University Taipei Taiwan TMU Research Center of Cancer Translational Medicine Taipei Medical University Taipei Taiwan Warshel Institute for Computational Biology The Chinese University of Hong Kong (Shenzhen) Guangdong Shenzhen China Biomedical Translation Research Center Academia Sinica Taipei Taiwan Division of Translational Toxicology National Institute of Environmental Health Sciences National Institutes of Health Durham NC United States School of Pharmacy College of Medicine National Taiwan University Taipei Taiwan Graduate Institute of Pharmacognosy College of Pharmacy Taipei Medical University Taipei Taiwan Cancer Center Wan Fang Hospital Taipei Medical University Taipei Taiwan

The identification of an effective inhibitor is an important starting step in drug development. Unfortunately, many issues such as the characterization of protein binding sites, the screening library, materials for assays, etc., make drug screening a difficult proposition. As the size of screening libraries increases, more resources will be inefficiently consumed. Thus, new strategies are needed to preprocess and focus a screening library towards a targeted protein. Herein, we report an ensemble machine learning (ML) model to generate a CdK8-focused screening library. The ensemble model consists of six different algorithms optimized for CdK8 inhibitor classification. The models were trained using a CdK8-specific fragment library along with molecules containing CdK8 activity. The optimized ensemble model processed a commercial library containing 1.6 million molecules. This resulted in a CdK8-focused screening library containing 1,672 molecules, a reduction of more than 99.90%. The CdK8-focused library was then subjected to molecular docking, and 25 candidate compounds were selected. Enzymatic assays confirmed six CdK8 inhibitors, with one compound producing an IC₅₀ value of ≤100 nM. Analysis of the ensemble ML model reveals the role of the CdK8 fragment library during training. Structural analysis of molecules reveals the hit compounds to be structurally novel CdK8 inhibitors. Together, the results highlight a pipeline for curating a focused library for a specific protein target, such as CdK8. © 2024 The Authors. Protein science published by Wiley Periodicals LLC on behalf of The Protein Society.

关键词： CdK8 fragment machine learning molecular docking structure-based virtual screening

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