{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T02:08:05Z","timestamp":1782439685013,"version":"3.54.5"},"reference-count":66,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,16]],"date-time":"2022-12-16T00:00:00Z","timestamp":1671148800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["22-75-10140"],"award-info":[{"award-number":["22-75-10140"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chronic liver diseases affect more than 1 billion people worldwide and represent one of the main public health issues. Nonalcoholic fatty liver disease (NAFLD) accounts for the majority of mortal cases, while there is no currently approved therapeutics for its treatment. One of the prospective approaches to NAFLD therapy is to use a mixture of natural compounds. They showed effectiveness in alleviating NAFLD-related conditions including steatosis, fibrosis, etc. However, understanding the mechanism of action of such mixtures is important for their rational application. In this work, we propose a new dereplication workflow for deciphering the mechanism of action of the lignin-derived natural compound mixture. The workflow combines the analysis of molecular components with high-resolution mass spectrometry, selective chemical tagging and deuterium labeling, liver tissue penetration examination, assessment of biological activity in vitro, and computational chemistry tools used to generate putative structural candidates. Molecular docking was used to propose the potential mechanism of action of these structures, which was assessed by a proteomic experiment.<\/jats:p>","DOI":"10.3390\/ijms232416025","type":"journal-article","created":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T04:54:13Z","timestamp":1671425653000},"page":"16025","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Hepatoprotective Activity of Lignin-Derived Polyphenols Dereplicated Using High-Resolution Mass Spectrometry, In Vivo Experiments, and Deep Learning"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7889-9245","authenticated-orcid":false,"given":"Alexey","family":"Orlov","sequence":"first","affiliation":[{"name":"Skolkovo Institute of Science and Technology, 30 Bolshoy Boulevard bld. 1, 121205 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9457-3210","authenticated-orcid":false,"given":"Savva","family":"Semenov","sequence":"additional","affiliation":[{"name":"Skolkovo Institute of Science and Technology, 30 Bolshoy Boulevard bld. 1, 121205 Moscow, Russia"},{"name":"Moscow Institute of Physics and Technology, 141701 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gleb","family":"Rukhovich","sequence":"additional","affiliation":[{"name":"Skolkovo Institute of Science and Technology, 30 Bolshoy Boulevard bld. 1, 121205 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Sarycheva","sequence":"additional","affiliation":[{"name":"Skolkovo Institute of Science and Technology, 30 Bolshoy Boulevard bld. 1, 121205 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oxana","family":"Kovaleva","sequence":"additional","affiliation":[{"name":"Skolkovo Institute of Science and Technology, 30 Bolshoy Boulevard bld. 1, 121205 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Semenov","sequence":"additional","affiliation":[{"name":"N.N. Petrov National Medical Research Center of Oncology, 68 Leningradskaya Str., 197758 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0259-2567","authenticated-orcid":false,"given":"Elena","family":"Ermakova","sequence":"additional","affiliation":[{"name":"N.N. Petrov National Medical Research Center of Oncology, 68 Leningradskaya Str., 197758 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina","family":"Gubareva","sequence":"additional","affiliation":[{"name":"N.N. Petrov National Medical Research Center of Oncology, 68 Leningradskaya Str., 197758 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1515-9447","authenticated-orcid":false,"given":"Anna E.","family":"Bugrova","sequence":"additional","affiliation":[{"name":"Emanuel Institute for Biochemical Physics, Russian Academy of Sciences, 119334 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey","family":"Kononikhin","sequence":"additional","affiliation":[{"name":"Skolkovo Institute of Science and Technology, 30 Bolshoy Boulevard bld. 1, 121205 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena I.","family":"Fedoros","sequence":"additional","affiliation":[{"name":"N.N. Petrov National Medical Research Center of Oncology, 68 Leningradskaya Str., 197758 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evgeny","family":"Nikolaev","sequence":"additional","affiliation":[{"name":"Skolkovo Institute of Science and Technology, 30 Bolshoy Boulevard bld. 1, 121205 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Zherebker","sequence":"additional","affiliation":[{"name":"Skolkovo Institute of Science and Technology, 30 Bolshoy Boulevard bld. 1, 121205 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e036663","DOI":"10.1136\/bmjopen-2019-036663","article-title":"Prevalence Trends in Non-Alcoholic Fatty Liver Disease at the Global, Regional and National Levels, 1990\u20132017: A Population-Based Observational Study","volume":"10","author":"Ge","year":"2020","journal-title":"BMJ Open"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e471","DOI":"10.1016\/S2214-109X(22)00047-X","article-title":"Chronic Liver Diseases Must Be Reduced Worldwide: It Is Time to Act","volume":"10","author":"Vento","year":"2022","journal-title":"Lancet Glob. Health"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/S2468-1253(22)00165-0","article-title":"The Prevalence and Incidence of NAFLD Worldwide: A Systematic Review and Meta-Analysis","volume":"7","author":"Riazi","year":"2022","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1159\/000323928","article-title":"Pathophysiology of Non-Alcoholic Steatohepatitis and Basis for Treatment","volume":"29","author":"Pinzani","year":"2011","journal-title":"Dig. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Umemura, A., Kataoka, S., Okuda, K., Seko, Y., Yamaguchi, K., Moriguchi, M., Okanoue, T., and Itoh, Y. (2022). Potential Therapeutic Targets and Promising Agents for Combating NAFLD. Biomedicines, 10.","DOI":"10.3390\/biomedicines10040901"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s43440-019-00020-1","article-title":"New Therapeutic Strategies in Nonalcoholic Fatty Liver Disease: A Focus on Promising Drugs for Nonalcoholic Steatohepatitis","volume":"72","author":"Pydyn","year":"2020","journal-title":"Pharmacol. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.ijbiomac.2016.01.109","article-title":"In Vitro Evaluation of Antioxidant and Cytotoxic Activities of Lignin Fractions Extracted from Acacia Nilotica","volume":"86","author":"Barapatre","year":"2016","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3389\/fnut.2018.00087","article-title":"The Role of Polyphenols in Human Health and Food Systems: A Mini-Review","volume":"5","author":"Cory","year":"2018","journal-title":"Front. Nutr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"27986","DOI":"10.1039\/C4RA13315C","article-title":"Free Radicals, Natural Antioxidants, and Their Reaction Mechanisms","volume":"5","author":"Pal","year":"2015","journal-title":"RSC Adv."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/s41573-021-00233-1","article-title":"Targeting Oxidative Stress in Disease: Promise and Limitations of Antioxidant Therapy","volume":"20","author":"Forman","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"110049","DOI":"10.1016\/j.envres.2020.110049","article-title":"Exploring Bioactivity Potential of Polyphenolic Water-Soluble Lignin Derivative","volume":"191","author":"Fedoros","year":"2020","journal-title":"Environ. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"14787","DOI":"10.3748\/wjg.v20.i40.14787","article-title":"Review of Natural Products with Hepatoprotective Effects","volume":"20","author":"Bautista","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"949746","DOI":"10.3389\/fimmu.2022.949746","article-title":"Efficacy and Safety of Dietary Polyphenol Supplementation in the Treatment of Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis","volume":"13","author":"Yang","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Abenavoli, L., Larussa, T., Corea, A., Procopio, A.C., Boccuto, L., Dallio, M., Federico, A., and Luzza, F. (2021). Dietary Polyphenols and Non-Alcoholic Fatty Liver Disease. Nutrients, 13.","DOI":"10.3390\/nu13020494"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s11101-015-9448-7","article-title":"Dereplication Strategies in Natural Product Research: How Many Tools and Methodologies behind the Same Concept?","volume":"16","author":"Hubert","year":"2017","journal-title":"Phytochem. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Wolfender, J.-L., Allard, P.-M., Kubo, M., and Queiroz, E.F. (2019). Metabolomics Strategies for the Dereplication of Polyphenols and Other Metabolites in Complex Natural Extracts. Recent Advances in Polyphenol Research, John Wiley & Sons, Ltd.","DOI":"10.1002\/9781119427896.ch7"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"D945","DOI":"10.1093\/nar\/gkw1074","article-title":"The ChEMBL Database in 2017","volume":"45","author":"Gaulton","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s13321-020-00478-9","article-title":"COCONUT Online: Collection of Open Natural Products Database","volume":"13","author":"Sorokina","year":"2021","journal-title":"J. Cheminform."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8908","DOI":"10.1021\/ac800464g","article-title":"Natural Organic Matter and the Event Horizon of Mass Spectrometry","volume":"80","author":"Hertkorn","year":"2008","journal-title":"Anal. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1021\/acs.est.1c04726","article-title":"Unsupervised Structural Classification of Dissolved Organic Matter Based on Fragmentation Pathways","volume":"56","author":"Leyva","year":"2022","journal-title":"Environ. Sci. Technol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2152","DOI":"10.1038\/s41598-022-06251-2","article-title":"Antiflammatory Activity and Potential Dermatological Applications of Characterized Humic Acids from a Lignite and a Green Compost","volume":"12","author":"Verrillo","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"109999","DOI":"10.1016\/j.envres.2020.109999","article-title":"New Artificial Network Model to Estimate Biological Activity of Peat Humic Acids","volume":"191","author":"Zykova","year":"2020","journal-title":"Environ. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"12066","DOI":"10.1038\/s41598-019-48000-y","article-title":"Examination of Molecular Space and Feasible Structures of Bioactive Components of Humic Substances by FTICR MS Data Mining in ChEMBL Database","volume":"9","author":"Orlov","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"23873","DOI":"10.1021\/acsomega.1c02841","article-title":"Inhibition of Class a \u03b2-Lactamase (TEM-1) by Narrow Fractions of Humic Substances","volume":"6","author":"Mikhnevich","year":"2021","journal-title":"ACS Omega"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Badun, G.A., Chernysheva, M.G., Zhernov, Y.V., Poroshina, A.S., Smirnov, V.V., Pigarev, S.E., Mikhnevich, T.A., Volkov, D.S., Perminova, I.V., and Fedoros, E.I. (2021). A Use of Tritium-Labeled Peat Fulvic Acids and Polyphenolic Derivatives for Designing Pharmacokinetic Experiments on Mice. Biomedicines, 9.","DOI":"10.3390\/biomedicines9121787"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"18578","DOI":"10.18632\/oncotarget.24990","article-title":"Novel Water-Soluble Lignin Derivative BP-Cx-1: Identification of Components and Screening of Potential Targets in Silico and in Vitro","volume":"9","author":"Fedoros","year":"2018","journal-title":"Oncotarget"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5171","DOI":"10.1073\/pnas.0813132106","article-title":"Bilirubin and Glutathione Have Complementary Antioxidant and Cytoprotective Roles","volume":"106","author":"Sedlak","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1021\/acscentsci.7b00512","article-title":"Generating Focused Molecule Libraries for Drug Discovery with Recurrent Neural Networks","volume":"4","author":"Segler","year":"2018","journal-title":"ACS Cent. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/s41573-018-0008-x","article-title":"Therapeutic Targeting of the NRF2 and KEAP1 Partnership in Chronic Diseases","volume":"18","author":"Cuadrado","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1111\/febs.15485","article-title":"Structural Insights into the Multiple Binding Modes of Dimethyl Fumarate (DMF) and Its Analogs to the Kelch Domain of Keap1","volume":"288","author":"Unni","year":"2021","journal-title":"FEBS J."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Cleasby, A., Yon, J., Day, P.J., Richardson, C., Tickle, I.J., Williams, P.A., Callahan, J.F., Carr, R., Concha, N., and Kerns, J.K. (2014). Structure of the BTB Domain of Keap1 and Its Interaction with the Triterpenoid Antagonist CDDO. PLoS ONE, 9.","DOI":"10.2210\/pdb4cxi\/pdb"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly Accurate Protein Structure Prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"ref_33","unstructured":"(2021, October 25). AlphaFold Protein Structure Database. Available online: https:\/\/alphafold.ebi.ac.uk\/."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.3389\/fphar.2018.01308","article-title":"The Role of Natural Products in Targeting Cardiovascular Diseases via Nrf2 Pathway: Novel Molecular Mechanisms and Therapeutic Approaches","volume":"9","author":"Ooi","year":"2018","journal-title":"Front Pharm."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1016\/j.biotechadv.2014.03.004","article-title":"Monitoring Keap1\u2013Nrf2 Interactions in Single Live Cells","volume":"32","author":"Baird","year":"2014","journal-title":"Biotechnol. Adv."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: Visual Molecular Dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graph."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1038\/nrd.2015.3","article-title":"Non-Alcoholic Steatohepatitis: Emerging Molecular Targets and Therapeutic Strategies","volume":"15","author":"Musso","year":"2016","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1146\/annurev.med.60.101107.134820","article-title":"Emerging Molecular Targets for the Treatment of Nonalcoholic Fatty Liver Disease","volume":"61","author":"Musso","year":"2010","journal-title":"Annu. Rev. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2707","DOI":"10.1016\/j.drudis.2021.05.019","article-title":"De Novo Molecular Design and Generative Models","volume":"26","author":"Meyers","year":"2021","journal-title":"Drug Discov. Today"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e8850","DOI":"10.1002\/rcm.8850","article-title":"Fourier Transform Ion Cyclotron Resonance Mass Spectrometry for the Analysis of Molecular Composition and Batch-to-Batch Consistency of Plant-Derived Polyphenolic Ligands Developed for Biomedical Application","volume":"34","author":"Zherebker","year":"2020","journal-title":"Rapid Commun. Mass Spectrom."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Vinardell, M.P., and Mitjans, M. (2017). Lignins and Their Derivatives with Beneficial Effects on Human Health. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18061219"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.nfs.2020.08.002","article-title":"Lignin is the Main Determinant of Total Dietary Fiber Differences between Date Fruit (Phoenix Dactylifera L.) Varieties","volume":"21","author":"George","year":"2020","journal-title":"NFS J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"9032","DOI":"10.1021\/acs.analchem.0c01208","article-title":"Refinement of Compound Aromaticity in Complex Organic Mixtures by Stable Isotope Label Assisted Ultrahigh-Resolution Mass Spectrometry","volume":"92","author":"Zherebker","year":"2020","journal-title":"Anal. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1039\/C9FD00002J","article-title":"Structural Investigation of Coal Humic Substances by Selective Isotopic Exchange and High-Resolution Mass Spectrometry","volume":"218","author":"Zherebker","year":"2019","journal-title":"Faraday Discuss."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2667","DOI":"10.1021\/acs.est.9b05298","article-title":"Optical Properties of Soil Dissolved Organic Matter Are Related to Acidic Functions of Its Components as Revealed by Fractionation, Selective Deuteromethylation, and Ultrahigh Resolution Mass Spectrometry","volume":"54","author":"Zherebker","year":"2020","journal-title":"Environ. Sci. Technol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2729","DOI":"10.1021\/acs.est.1c04575","article-title":"Aromaticity Index with Improved Estimation of Carboxyl Group Contribution for Biogeochemical Studies","volume":"56","author":"Zherebker","year":"2022","journal-title":"Environ. Sci. Technol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Joost, H.-G., Al-Hasani, H., and Sch\u00fcrmann, A. (2012). Experimentally Induced Rodent Models of Type 2 Diabetes. Animal Models in Diabetes Research, Humana Press. Methods in Molecular Biology.","DOI":"10.1007\/978-1-62703-068-7"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e78","DOI":"10.1002\/cpz1.78","article-title":"Streptozotocin-Induced Diabetic Models in Mice and Rats","volume":"1","author":"Furman","year":"2021","journal-title":"Curr. Protoc."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"D1100","DOI":"10.1093\/nar\/gkr777","article-title":"ChEMBL: A Large-Scale Bioactivity Database for Drug Discovery","volume":"40","author":"Gaulton","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_50","unstructured":"(2021, September 01). ChEMBL Ftp Site. Available online: https:\/\/ftp.ebi.ac.uk\/pub\/databases\/chembl\/ChEMBLdb\/releases\/chembl_29\/."},{"key":"ref_51","unstructured":"(2021, October 25). Mysql-Connector-Python Library. Available online: https:\/\/pypi.org\/project\/mysql-connector-python\/."},{"key":"ref_52","unstructured":"McKinney, W. (July, January 28). Data Structures for Statistical Computing in Python. Proceedings of the 9th Python in Science Conference, Austin, TX, USA."},{"key":"ref_53","unstructured":"Team, T.P.D. (2021, October 25). Pandas Python Library. Available online: https:\/\/pandas.pydata.org\/."},{"key":"ref_54","unstructured":"(2021, October 25). RDKit: Open-Source Cheminformatics. Available online: http:\/\/Www.Rdkit.Org."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1021\/ci500588j","article-title":"DataWarrior: An Open-Source Program for Chemistry Aware Data Visualization and Analysis","volume":"55","author":"Sander","year":"2015","journal-title":"J. Chem. Inf. Model."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"The UniProt Consortium, Bateman, A., Martin, M.-J., Orchard, S., Magrane, M., Agivetova, R., Ahmad, S., Alpi, E., and Bowler-Barnett, E.H. (2021). UniProt: The Universal Protein Knowledgebase in 2021. Nucleic Acids Res., 49, D480\u2013D489.","DOI":"10.1093\/nar\/gkaa1100"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Eastman, P., Swails, J., Chodera, J.D., McGibbon, R.T., Zhao, Y., Beauchamp, K.A., Wang, L.-P., Simmonett, A.C., Harrigan, M.P., and Stern, C.D. (2017). OpenMM 7: Rapid Development of High Performance Algorithms for Molecular Dynamics. PLoS Comput. Biol., 13.","DOI":"10.1371\/journal.pcbi.1005659"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1007\/BF00228148","article-title":"AQUA and PROCHECK-NMR: Programs for Checking the Quality of Protein Structures Solved by NMR","volume":"8","author":"Laskowski","year":"1996","journal-title":"J. Biomol. NMR"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"W407","DOI":"10.1093\/nar\/gkm290","article-title":"ProSA-Web: Interactive Web Service for the Recognition of Errors in Three-Dimensional Structures of Proteins","volume":"35","author":"Wiederstein","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1002\/prot.340170404","article-title":"Recognition of Errors in Three-Dimensional Structures of Proteins","volume":"17","author":"Sippl","year":"1993","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Le Guilloux, V., Schmidtke, P., and Tuffery, P. (2009). Fpocket: An Open Source Platform for Ligand Pocket Detection. BMC Bioinform., 10.","DOI":"10.1186\/1471-2105-10-168"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1758-2946-3-33","article-title":"Open Babel: An Open Chemical Toolbox","volume":"3","author":"Banck","year":"2011","journal-title":"J. Cheminform."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization and Multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"3891","DOI":"10.1021\/acs.jcim.1c00203","article-title":"AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings","volume":"61","author":"Eberhardt","year":"2021","journal-title":"J. Chem. Inf. Model."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2981","DOI":"10.1093\/bioinformatics\/btu426","article-title":"YASARA View\u2014Molecular Graphics for All Devices\u2014From Smartphones to Workstations","volume":"30","author":"Krieger","year":"2014","journal-title":"Bioinformatics"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/24\/16025\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:42:45Z","timestamp":1760146965000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/24\/16025"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,16]]},"references-count":66,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["ijms232416025"],"URL":"https:\/\/doi.org\/10.3390\/ijms232416025","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,16]]}}}