{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T23:34:38Z","timestamp":1785540878272,"version":"3.56.0"},"reference-count":79,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T00:00:00Z","timestamp":1762905600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T00:00:00Z","timestamp":1762905600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Cholera, a life-threatening diarrheal disease caused by Vibrio cholerae, remains a global health concern. Traditional medicinal plants such as\n                    <jats:italic>Berberis vulgaris<\/jats:italic>\n                    (barberry) and\n                    <jats:italic>Hydrastis canadensis<\/jats:italic>\n                    (goldenseal) have long been used for their antimicrobial properties. This study employed integrated computational approaches to identify potential anti-cholera compounds from these plants by targeting sodium-pumping NADH-ubiquinone oxidoreductase (Na\u207a-NQR). Virtual screening identified compounds\n                    <jats:bold>122623<\/jats:bold>\n                    ,\n                    <jats:bold>197835<\/jats:bold>\n                    , and\n                    <jats:bold>638024<\/jats:bold>\n                    , along with the control Korormicin, exhibiting favorable binding affinities and hydrogen bonding interactions. Machine learning-based prediction models were further applied to assess functional activity and binding affinity. The study incorporated ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiling and density functional theory (DFT) calculations to evaluate physicochemical properties and electronic characteristics of the compounds. Molecular dynamics (MD) simulations demonstrated stable RMSD values for the ligands, with\n                    <jats:bold>122623<\/jats:bold>\n                    exhibiting the lowest RMSD (0.3\u20130.5\u00a0nm), closely resembling the control (0.3\u20130.4\u00a0nm), suggesting stable binding. Principal component analysis (PCA) showed tight conformational clusters for complexes with\n                    <jats:bold>122623<\/jats:bold>\n                    and\n                    <jats:bold>197835<\/jats:bold>\n                    , while free energy landscape (FEL) analysis revealed deep energy minima, supporting complex stability. MM\/GBSA calculations showed that\n                    <jats:bold>122623<\/jats:bold>\n                    had the lowest binding free energy (-38.71\u00a0kcal\/mol), followed by\n                    <jats:bold>638024<\/jats:bold>\n                    (-35.14\u00a0kcal\/mol) and\n                    <jats:bold>197835<\/jats:bold>\n                    (-30.68\u00a0kcal\/mol). Per-residue energy decomposition identified key residues (Phe137, Val155, Phe159, Phe160) involved in ligand binding. Network pharmacology analysis predicted additional gene targets for the selected compounds, providing insights into their broader therapeutic relevance. Collectively, compounds\n                    <jats:bold>122623<\/jats:bold>\n                    ,\n                    <jats:bold>197835<\/jats:bold>\n                    , and\n                    <jats:bold>638024<\/jats:bold>\n                    derived from\n                    <jats:italic>Hydrastis canadensis<\/jats:italic>\n                    and\n                    <jats:italic>Berberis vulgaris<\/jats:italic>\n                    demonstrated promising inhibitory interactions with the Na\u207a-NQR enzyme, suggesting their potential as anti-cholera agents.\n                  <\/jats:p>","DOI":"10.1038\/s41598-025-23546-2","type":"journal-article","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T18:53:25Z","timestamp":1762973605000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Machine learning-guided in Silico identification of Na\u207a-NQR inhibitors from Berberis vulgaris and Hydrastis Canadensis phytochemicals against Vibrio cholerae"],"prefix":"10.1038","volume":"15","author":[{"given":"Leena H.","family":"Bajrai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai M.","family":"El-Daly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim A.","family":"AL-Zahrani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amira M.","family":"Alghamdi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isra M.","family":"Alsaady","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivek Dhar","family":"Dwivedi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esam I.","family":"Azhar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,12]]},"reference":[{"key":"23546_CR1","doi-asserted-by":"publisher","first-page":"e0003832","DOI":"10.1371\/journal.pntd.0003832","volume":"9","author":"M Ali","year":"2015","unstructured":"Ali, M., Nelson, A. R., Lopez, A. L. & Sack, D. A. Updated global burden of cholera in endemic countries. PLoS Negl. Trop. Dis. 9, e0003832 (2015).","journal-title":"PLoS Negl. Trop. Dis."},{"key":"23546_CR2","unstructured":"New analysis confirms world seeing an upsurge of cholera. https:\/\/www.who.int\/news\/item\/22-09-2023-new-analysis-confirms-world-seeing-an-upsurge-of-cholera"},{"key":"23546_CR3","unstructured":"Multi-country cholera outbreak, external situation report #22\u201324. January (2025). https:\/\/www.who.int\/publications\/m\/item\/multi-country-cholera-outbreak--external-situation-report--22---24-january-2025"},{"key":"23546_CR4","unstructured":"Multi-country outbreak of cholera, External situation report #20\u201320. November (2024). https:\/\/www.who.int\/publications\/m\/item\/multi-country-outbreak-of-cholera--external-situation-report--20---20-november-2024"},{"key":"23546_CR5","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.mjafi.2014.04.011","volume":"71","author":"AK Jindal","year":"2015","unstructured":"Jindal, A. K., Pandya, K. & Khan, I. D. Antimicrobial resistance: A public health challenge. Med. J. Armed Forces India. 71, 178\u2013181 (2015).","journal-title":"Med. J. Armed Forces India"},{"key":"23546_CR6","doi-asserted-by":"publisher","first-page":"14","DOI":"10.3390\/microorganisms4010014","volume":"4","author":"P Blanco","year":"2016","unstructured":"Blanco, P. et al. Bacterial multidrug efflux pumps: much more than antibiotic resistance determinants. Microorganisms 4, 14 (2016).","journal-title":"Microorganisms"},{"key":"23546_CR7","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1038\/nature14003","volume":"516","author":"J Steuber","year":"2014","unstructured":"Steuber, J. et al. Structure of the V. cholerae Na+-pumping nadh:quinone oxidoreductase. Nature 516, 62\u201367 (2014).","journal-title":"Nature"},{"key":"23546_CR8","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1007\/s10863-014-9565-9","volume":"46","author":"B Barquera","year":"2014","unstructured":"Barquera, B. The sodium pumping nadh:quinone oxidoreductase (Na+-NQR), a unique redox-driven ion pump. J. Bioenerg Biomembr. 46, 289\u2013298 (2014).","journal-title":"J. Bioenerg Biomembr."},{"key":"23546_CR9","doi-asserted-by":"publisher","first-page":"12505","DOI":"10.1073\/pnas.1002866107","volume":"107","author":"O Ju\u00e1rez","year":"2010","unstructured":"Ju\u00e1rez, O., Morgan, J. E., Nilges, M. J. & Barquera, B. Energy transducing redox steps of the Na+-pumping nadh:quinone oxidoreductase from vibrio cholerae. Proc. Natl. Acad. Sci. U S A. 107, 12505\u201312510 (2010).","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"23546_CR10","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/S0005-2728(00)00286-3","volume":"1505","author":"CC H\u00e4se","year":"2001","unstructured":"H\u00e4se, C. C. & Barquera, B. Role of sodium bioenergetics in vibrio cholerae. Biochim. Biophys. Acta. 1505, 169\u2013178 (2001).","journal-title":"Biochim. Biophys. Acta"},{"key":"23546_CR11","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1093\/femsre\/fux032","volume":"41","author":"P Dibrov","year":"2017","unstructured":"Dibrov, P., Dibrov, E. & Pierce, G. N. Na+-NQR (Na+-translocating nadh:ubiquinone oxidoreductase) as a novel target for antibiotics. FEMS Microbiol. Rev. 41, 653\u2013671 (2017).","journal-title":"FEMS Microbiol. Rev."},{"key":"23546_CR12","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/S0005-2728(00)00275-9","volume":"1505","author":"M Hayashi","year":"2001","unstructured":"Hayashi, M., Nakayama, Y. & Unemoto, T. Recent progress in the Na+-translocating NADH-quinone reductase from the marine vibrio alginolyticus. Biochimica Et Biophys. Acta (BBA) - Bioenergetics. 1505, 37\u201344 (2001).","journal-title":"Biochimica Et Biophys. Acta (BBA) - Bioenergetics"},{"key":"23546_CR13","doi-asserted-by":"publisher","first-page":"1823","DOI":"10.1016\/j.bbabio.2012.03.017","volume":"1817","author":"O Ju\u00e1rez","year":"2012","unstructured":"Ju\u00e1rez, O. & Barquera, B. Insights into the mechanism of electron transfer and sodium translocation of the Na+-pumping nadh:quinone oxidoreductase. Biochimica Et Biophys. Acta (BBA) - Bioenergetics. 1817, 1823\u20131832 (2012).","journal-title":"Biochimica Et Biophys. Acta (BBA) - Bioenergetics"},{"key":"23546_CR14","doi-asserted-by":"publisher","first-page":"4082","DOI":"10.1038\/s41467-022-31718-1","volume":"13","author":"J Kishikawa","year":"2022","unstructured":"Kishikawa, J. et al. Cryo-EM structures of Na+-pumping NADH-ubiquinone oxidoreductase from vibrio cholerae. Nat. Commun. 13, 4082 (2022).","journal-title":"Nat. Commun."},{"key":"23546_CR15","doi-asserted-by":"publisher","first-page":"8963","DOI":"10.1074\/jbc.M809395200","volume":"284","author":"O Ju\u00e1rez","year":"2009","unstructured":"Ju\u00e1rez, O., Morgan, J. E. & Barquera, B. The electron transfer pathway of the Na+-pumping nadh:quinone oxidoreductase from vibrio cholerae. J. Biol. Chem. 284, 8963\u20138972 (2009).","journal-title":"J. Biol. Chem."},{"key":"23546_CR16","doi-asserted-by":"publisher","first-page":"12739","DOI":"10.1074\/jbc.RA120.014229","volume":"295","author":"T Masuya","year":"2020","unstructured":"Masuya, T. et al. Inhibitors of a Na+-pumping NADH-ubiquinone oxidoreductase play multiple roles to block enzyme function. J. Biol. Chem. 295, 12739\u201312754 (2020).","journal-title":"J. Biol. Chem."},{"key":"23546_CR17","doi-asserted-by":"publisher","first-page":"1471","DOI":"10.1046\/j.1365-2958.2002.02857.x","volume":"43","author":"DS Merrell","year":"2002","unstructured":"Merrell, D. S., Hava, D. L. & Camilli, A. Identification of novel factors involved in colonization and acid tolerance of vibrio cholerae. Mol. Microbiol. 43, 1471\u20131491 (2002).","journal-title":"Mol. Microbiol."},{"key":"23546_CR18","doi-asserted-by":"publisher","first-page":"4082","DOI":"10.1038\/s41467-022-31718-1","volume":"13","author":"JI Kishikawa","year":"2022","unstructured":"Kishikawa, J. I. et al. Cryo-EM structures of Na+-pumping NADH-ubiquinone oxidoreductase from vibrio cholerae. Nat. Commun. 13, 4082 (2022).","journal-title":"Nat. Commun."},{"key":"23546_CR19","doi-asserted-by":"crossref","unstructured":"Maynard, A. et al. Antibiotic korormicin A kills bacteria by producing reactive oxygen species. J Bacteriol. 201 (11), e00718-18 (2019).","DOI":"10.1128\/JB.00718-18"},{"key":"23546_CR20","doi-asserted-by":"publisher","first-page":"1064","DOI":"10.1248\/bpb.22.1064","volume":"22","author":"Y Nakayama","year":"1999","unstructured":"Nakayama, Y., Hayashi, M., Yoshikawa, K., Mochida, K. & Unemoto, T. Inhibitor studies of a new Antibiotic, Korormicin, 2-n-Heptyl-4-hydroxyquinoline N-oxide and Ag\u2009<\u2009SUP>+\u2009toward the Na\u2009<\u2009SUP>+-Translocating NADH-Quinone reductase from the marine vibrio alginolyticus. Biological Pharmaceutical Bulletin. 22, 1064\u20131067 (1999).","journal-title":"Biological Pharmaceutical Bulletin"},{"key":"23546_CR21","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1111\/j.1574-6968.2007.01015.x","volume":"279","author":"MS Fadeeva","year":"2008","unstructured":"Fadeeva, M. S., N\u00fa\u00f1ez, C., Bertsova, Y. V., Esp\u00edn, G. & Bogachev, A. V. Catalytic properties of Na+-translocating nadh:quinone oxidoreductases from vibrio harveyi, Klebsiella pneumoniae, and azotobacter vinelandii. FEMS Microbiol. Lett. 279, 116\u2013123 (2008).","journal-title":"FEMS Microbiol. Lett."},{"key":"23546_CR22","doi-asserted-by":"publisher","first-page":"7727","DOI":"10.1074\/jbc.M117.781393","volume":"292","author":"T Ito","year":"2017","unstructured":"Ito, T. et al. Identification of the binding sites for ubiquinone and inhibitors in the Na+-pumping NADH-ubiquinone oxidoreductase from vibrio cholerae by photoaffinity labeling. J. Biol. Chem. 292, 7727\u20137742 (2017).","journal-title":"J. Biol. Chem."},{"key":"23546_CR23","doi-asserted-by":"publisher","DOI":"10.1101\/2025.06.01.656757","author":"M Ishikawa-Fukuda","year":"2025","unstructured":"Ishikawa-Fukuda, M. et al. The Na+ -pumping mechanism driven by redox reactions in the NADH-quinone oxidoreductase from Vibrio cholerae relies on dynamic conformational changes. Preprint at. https:\/\/doi.org\/10.1101\/2025.06.01.656757 (2025).","journal-title":"Preprint at."},{"key":"23546_CR24","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1128\/iai.35.2.471-475.1982","volume":"35","author":"RB Sack","year":"1982","unstructured":"Sack, R. B. & Froehlich, J. L. Berberine inhibits intestinal secretory response of vibrio cholerae and Escherichia coli enterotoxins. Infect. Immun. 35, 471\u2013475 (1982).","journal-title":"Infect. Immun."},{"key":"23546_CR25","doi-asserted-by":"crossref","unstructured":"Han, M. et al. Effect of Berberine hydrochloride treatment on transcriptomic response in gill tissue of Charybdis Japonica infected with Aeromonas hydrophila. Front. Mar. Sci. 8, 754588 (2021).","DOI":"10.3389\/fmars.2021.754588"},{"key":"23546_CR26","unstructured":"Berberis vulgaris -. an overview | ScienceDirect Topics. https:\/\/www.sciencedirect.com\/topics\/immunology-and-microbiology\/berberis-vulgaris"},{"key":"23546_CR27","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1055\/s-0030-1250606","volume":"77","author":"KA Ettefagh","year":"2011","unstructured":"Ettefagh, K. A., Burns, J. T., Junio, H. A., Kaatz, G. W. & Cech, N. B. Goldenseal (Hydrastis Canadensis L.) extracts synergistically enhance the antibacterial activity of Berberine via efflux pump Inhibition. Planta Med. 77, 835\u2013840 (2011).","journal-title":"Planta Med."},{"key":"23546_CR28","first-page":"175","volume":"5","author":"Berberine","year":"2000","unstructured":"Berberine Altern. Med. Rev. 5, 175\u2013177 (2000).","journal-title":"Altern. Med. Rev."},{"key":"23546_CR29","unstructured":"Berberine. in. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury (National Institute of Diabetes and Digestive and Kidney Diseases, 2012)."},{"key":"23546_CR30","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1093\/nar\/28.1.235","volume":"28","author":"HM Berman","year":"2000","unstructured":"Berman, H. M. et al. The protein data bank. Nucleic Acids Res. 28, 235\u2013242 (2000).","journal-title":"Nucleic Acids Res."},{"key":"23546_CR31","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1128\/CMR.12.4.564","volume":"12","author":"MM Cowan","year":"1999","unstructured":"Cowan, M. M. Plant products as antimicrobial agents. Clin. Microbiol. Rev. 12, 564\u2013582 (1999).","journal-title":"Clin. Microbiol. Rev."},{"key":"23546_CR32","doi-asserted-by":"publisher","first-page":"6114","DOI":"10.3390\/molecules27186114","volume":"27","author":"KM El-Zahar","year":"2022","unstructured":"El-Zahar, K. M. et al. Antioxidant, Antibacterial, and antifungal activities of the ethanolic extract obtained from berberis vulgaris roots and leaves. Molecules 27, 6114 (2022).","journal-title":"Molecules"},{"key":"23546_CR33","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1002\/ptr.2968","volume":"24","author":"SK Kulkarni","year":"2010","unstructured":"Kulkarni, S. K. & Dhir, A. Berberine: a plant alkaloid with therapeutic potential for central nervous system disorders. Phytother Res. 24, 317\u2013324 (2010).","journal-title":"Phytother Res."},{"key":"23546_CR34","doi-asserted-by":"publisher","first-page":"100507","DOI":"10.1016\/j.prmcm.2024.100507","volume":"13","author":"A Phogat","year":"2024","unstructured":"Phogat, A., Singh, J. & Malik, V. Pharmacological effects of Berberine \u2013 A Chinese medicine, against xenobiotics toxicity. Pharmacological Research - Modern Chin. Medicine. 13, 100507 (2024).","journal-title":"Pharmacological Research - Modern Chin. Medicine"},{"key":"23546_CR35","doi-asserted-by":"publisher","first-page":"1370","DOI":"10.1128\/AAC.32.9.1370","volume":"32","author":"D Sun","year":"1988","unstructured":"Sun, D., Courtney, H. S. & Beachey, E. H. Berberine sulfate blocks adherence of Streptococcus pyogenes to epithelial cells, fibronectin, and hexadecane. Antimicrob. Agents Chemother. 32, 1370\u20131374 (1988).","journal-title":"Antimicrob. Agents Chemother."},{"key":"23546_CR36","doi-asserted-by":"publisher","first-page":"105085","DOI":"10.1016\/j.phrs.2020.105085","volume":"160","author":"SK Mandal","year":"2020","unstructured":"Mandal, S. K. et al. Goldenseal (Hydrastis Canadensis L.) and its active constituents: A critical review of their efficacy and toxicological issues. Pharmacol. Res. 160, 105085 (2020).","journal-title":"Pharmacol. Res."},{"key":"23546_CR37","doi-asserted-by":"publisher","first-page":"D621","DOI":"10.1093\/nar\/gkac1069","volume":"51","author":"H Zhao","year":"2023","unstructured":"Zhao, H. et al. NPASS database update 2023: quantitative natural product activity and species source database for biomedical research. Nucleic Acids Res. 51, D621\u2013D628 (2023).","journal-title":"Nucleic Acids Res."},{"key":"23546_CR38","doi-asserted-by":"publisher","first-page":"D1217","DOI":"10.1093\/nar\/gkx1026","volume":"46","author":"X Zeng","year":"2018","unstructured":"Zeng, X. et al. NPASS: natural product activity and species source database for natural product research, discovery and tool development. Nucleic Acids Res. 46, D1217\u2013D1222 (2018).","journal-title":"Nucleic Acids Res."},{"key":"23546_CR39","doi-asserted-by":"publisher","unstructured":"Greg et al. rdkit\/rdkit: 2023_09_2 (Q3 2023) Release. Zenodo (2023). https:\/\/doi.org\/10.5281\/ZENODO.10099869","DOI":"10.5281\/ZENODO.10099869"},{"key":"23546_CR40","unstructured":"Pedregosa, F. et al. Scikit-learn: Machine learning in Python. Journal of Machine Learning Research 2825\u20132830 (2011)."},{"key":"23546_CR41","doi-asserted-by":"publisher","first-page":"2785","DOI":"10.1002\/jcc.21256","volume":"30","author":"GM Morris","year":"2009","unstructured":"Morris, G. M. et al. AutoDock4 and AutoDockTools4: automated Docking with selective receptor flexibility. J. Comput. Chem. 30, 2785\u20132791 (2009).","journal-title":"J. Comput. Chem."},{"key":"23546_CR42","doi-asserted-by":"publisher","first-page":"3891","DOI":"10.1021\/acs.jcim.1c00203","volume":"61","author":"J Eberhardt","year":"2021","unstructured":"Eberhardt, J., Santos-Martins, D., F Tillack, A. & Forli, S. AutoDock Vina 1.2.0: new Docking Methods, expanded force Field, and python bindings. J. Chem. Inf. Model. 61, 3891\u20133898 (2021).","journal-title":"J. Chem. Inf. Model."},{"key":"23546_CR43","doi-asserted-by":"publisher","first-page":"42717","DOI":"10.1038\/srep42717","volume":"7","author":"A Daina","year":"2017","unstructured":"Daina, A., Michielin, O. & Zoete, V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 7, 42717 (2017).","journal-title":"Sci. Rep."},{"key":"23546_CR44","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1016\/S1359-6446(04)03069-7","volume":"9","author":"AL Hopkins","year":"2004","unstructured":"Hopkins, A. L., Groom, C. R. & Alex, A. Ligand efficiency: a useful metric for lead selection. Drug Discovery Today. 9, 430\u2013431 (2004).","journal-title":"Drug Discovery Today"},{"key":"23546_CR45","doi-asserted-by":"publisher","first-page":"10037","DOI":"10.1073\/pnas.181342398","volume":"98","author":"NA Baker","year":"2001","unstructured":"Baker, N. A., Sept, D., Joseph, S., Holst, M. J. & McCammon, J. A. Electrostatics of nanosystems: application to microtubules and the ribosome. Proc. Natl. Acad. Sci. U S A. 98, 10037\u201310041 (2001).","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"23546_CR46","doi-asserted-by":"publisher","first-page":"2540","DOI":"10.1021\/acs.jchemed.9b00143","volume":"96","author":"JE Lineback","year":"2019","unstructured":"Lineback, J. E. & Jansma, A. L. PyMOL as an instructional tool to represent and manipulate the Myoglobin\/Hemoglobin protein system. J. Chem. Educ. 96, 2540\u20132544 (2019).","journal-title":"J. Chem. Educ."},{"key":"23546_CR47","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1002\/pro.3280","volume":"27","author":"E Jurrus","year":"2018","unstructured":"Jurrus, E. et al. Improvements to the APBS biomolecular solvation software suite. Protein Sci. 27, 112\u2013128 (2018).","journal-title":"Protein Sci."},{"key":"23546_CR48","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1038\/s42256-024-00847-1","volume":"6","author":"HY Koh","year":"2024","unstructured":"Koh, H. Y., Nguyen, A. T. N., Pan, S., May, L. T. & Webb, G. I. Physicochemical graph neural network for learning protein\u2013ligand interaction fingerprints from sequence data. Nat. Mach. Intell. 6, 673\u2013687 (2024).","journal-title":"Nat. Mach. Intell."},{"key":"23546_CR49","doi-asserted-by":"publisher","first-page":"W257","DOI":"10.1093\/nar\/gky318","volume":"46","author":"P Banerjee","year":"2018","unstructured":"Banerjee, P., Eckert, A. O., Schrey, A. K. & Preissner, R. ProTox-II: a webserver for the prediction of toxicity of chemicals. Nucleic Acids Res. 46, W257\u2013W263 (2018).","journal-title":"Nucleic Acids Res."},{"key":"23546_CR50","doi-asserted-by":"publisher","first-page":"4066","DOI":"10.1021\/acs.jmedchem.5b00104","volume":"58","author":"DEV Pires","year":"2015","unstructured":"Pires, D. E. V., Blundell, T. L. & Ascher, D. B. PkCSM: predicting Small-Molecule Pharmacokinetic and toxicity properties using Graph-Based signatures. J. Med. Chem. 58, 4066\u20134072 (2015).","journal-title":"J. Med. Chem."},{"key":"23546_CR51","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1119\/1.19375","volume":"68","author":"N Argaman","year":"2000","unstructured":"Argaman, N. & Makov, G. Density functional theory: an introduction. Am. J. Phys. 68, 69\u201379 (2000).","journal-title":"Am. J. Phys."},{"key":"23546_CR52","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1007\/978-94-017-9257-8_7","volume-title":"Application of Computational Techniques in Pharmacy and Medicine","author":"AB Rozhenko","year":"2014","unstructured":"Rozhenko, A. B. Density functional theory calculations of Enzyme\u2013Inhibitor interactions in medicinal chemistry and drug design. In Application of Computational Techniques in Pharmacy and Medicine (eds Gorb, L. et al.) 207\u2013240 (Springer Netherlands, 2014). https:\/\/doi.org\/10.1007\/978-94-017-9257-8_7."},{"key":"23546_CR53","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1021\/ct700248k","volume":"4","author":"J Tirado-Rives","year":"2008","unstructured":"Tirado-Rives, J. & Jorgensen, W. L. Performance of B3LYP density functional methods for a large set of organic molecules. J. Chem. Theory Comput. 4, 297\u2013306 (2008).","journal-title":"J. Chem. Theory Comput."},{"key":"23546_CR54","doi-asserted-by":"crossref","unstructured":"Grossman, E. F., Daramola, D. A. & Botte, G. G. Comparing B3LYP and B97 Dispersion-corrected Functionals for Studying Adsorption and Vibrational Spectra in Nitrogen Reduction. ChemistryOpen 10, 316\u2013326 (2021).","DOI":"10.1002\/open.202000158"},{"key":"23546_CR55","doi-asserted-by":"publisher","first-page":"e1340","DOI":"10.1002\/wcms.1340","volume":"8","author":"Q Sun","year":"2018","unstructured":"Sun, Q. et al. PySCF: the Python-based simulations of chemistry framework. WIREs Comput. Mol. Sci. 8, e1340 (2018).","journal-title":"WIREs Comput. Mol. Sci."},{"key":"23546_CR56","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/S0022-3093(00)00306-9","volume":"277","author":"JM Nedelec","year":"2000","unstructured":"Nedelec, J. M. & Hench, L. L. Effect of basis set and of electronic correlation on Ab initio calculations on silica rings. J. Non-cryst. Solids. 277, 106\u2013113 (2000).","journal-title":"J. Non-cryst. Solids"},{"key":"23546_CR57","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1021\/ct700301q","volume":"4","author":"B Hess","year":"2008","unstructured":"Hess, B., Kutzner, C., van der Spoel, D. & Lindahl, E. GROMACS 4: algorithms for highly Efficient, Load-Balanced, and scalable molecular simulation. J. Chem. Theory Comput. 4, 435\u2013447 (2008).","journal-title":"J. Chem. Theory Comput."},{"key":"23546_CR58","doi-asserted-by":"crossref","unstructured":"Berendsen, H. J. C., van der Spoel, D. & van Drunen R. GROMACS: A message-passing parallel molecular dynamics implementation. Computer Physics Communications 91, 43\u201356 (1995).","DOI":"10.1016\/0010-4655(95)00042-E"},{"key":"23546_CR59","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","volume":"GROMACS","author":"MJ Abraham","year":"2015","unstructured":"Abraham, M. J. et al. High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1. GROMACS, 19\u201325 (2015).","journal-title":"SoftwareX 1"},{"key":"23546_CR60","doi-asserted-by":"publisher","unstructured":"Lindahl Abraham, Hess & Van Der Spoel. GROMACS 2021.2 Manual. (2021). https:\/\/doi.org\/10.5281\/ZENODO.4723561","DOI":"10.5281\/ZENODO.4723561"},{"key":"23546_CR61","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1002\/jcc.21367","volume":"31","author":"K Vanommeslaeghe","year":"2010","unstructured":"Vanommeslaeghe, K. et al. CHARMM general force field (CGenFF): A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J. Comput. Chem. 31, 671\u2013690 (2010).","journal-title":"J. Comput. Chem."},{"key":"23546_CR62","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1021\/ct900549r","volume":"6","author":"P Bjelkmar","year":"2010","unstructured":"Bjelkmar, P., Larsson, P., Cuendet, M. A., Hess, B. & Lindahl, E. Implementation of the CHARMM force field in GROMACS: analysis of protein stability effects from correction Maps, virtual interaction Sites, and water models. J. Chem. Theory Comput. 6, 459\u2013466 (2010).","journal-title":"J. Chem. Theory Comput."},{"key":"23546_CR63","doi-asserted-by":"publisher","first-page":"2359","DOI":"10.1002\/jcc.21816","volume":"32","author":"V Zoete","year":"2011","unstructured":"Zoete, V., Cuendet, M. A., Grosdidier, A., Michielin, O. & SwissParam A fast force field generation tool for small organic molecules. J. Comput. Chem. 32, 2359\u20132368 (2011).","journal-title":"J. Comput. Chem."},{"key":"23546_CR64","doi-asserted-by":"publisher","first-page":"10089","DOI":"10.1063\/1.464397","volume":"98","author":"T Darden","year":"1993","unstructured":"Darden, T., York, D. & Pedersen, L. Particle mesh ewald: an N\u22c5log(N) method for Ewald sums in large systems. J. Chem. Phys. 98, 10089\u201310092 (1993).","journal-title":"J. Chem. Phys."},{"key":"23546_CR65","doi-asserted-by":"publisher","first-page":"3863","DOI":"10.1021\/jz501780a","volume":"5","author":"S Izadi","year":"2014","unstructured":"Izadi, S., Anandakrishnan, R. & Onufriev, A. V. Building water models: A different approach. J. Phys. Chem. Lett. 5, 3863\u20133871 (2014).","journal-title":"J. Phys. Chem. Lett."},{"key":"23546_CR66","doi-asserted-by":"publisher","first-page":"5113","DOI":"10.1021\/jp508971m","volume":"119","author":"S Piana","year":"2015","unstructured":"Piana, S., Donchev, A. G., Robustelli, P. & Shaw, D. E. Water dispersion interactions strongly influence simulated structural properties of disordered protein States. J. Phys. Chem. B. 119, 5113\u20135123 (2015).","journal-title":"J. Phys. Chem. B"},{"key":"23546_CR67","doi-asserted-by":"publisher","first-page":"2620","DOI":"10.1021\/acs.jctc.8b01123","volume":"15","author":"PS Shabane","year":"2019","unstructured":"Shabane, P. S., Izadi, S. & Onufriev, A. V. General purpose water model can improve atomistic simulations of intrinsically disordered proteins. J. Chem. Theory Comput. 15, 2620\u20132634 (2019).","journal-title":"J. Chem. Theory Comput."},{"key":"23546_CR68","doi-asserted-by":"publisher","unstructured":"Falato, M., Chen, L. Y., Chan, R. & Liang, H. TIP3P and TIP4P in molecular dynamics simulations of erythrocyte Aquaporins. TACCSTER 2020 Proceedings (2020). https:\/\/doi.org\/10.26153\/tsw\/11475","DOI":"10.26153\/tsw\/11475"},{"key":"23546_CR69","doi-asserted-by":"publisher","first-page":"1463","DOI":"10.1002\/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H","volume":"18","author":"B Hess","year":"1997","unstructured":"Hess, B., Bekker, H., Berendsen, H. J. C. & Fraaije, J. G. E. M. LINCS: A linear constraint solver for molecular simulations. J. Comput. Chem. 18, 1463\u20131472 (1997).","journal-title":"J. Comput. Chem."},{"key":"23546_CR70","doi-asserted-by":"publisher","first-page":"7182","DOI":"10.1063\/1.328693","volume":"52","author":"M Parrinello","year":"1981","unstructured":"Parrinello, M. & Rahman, A. Polymorphic transitions in single crystals: A new molecular dynamics method. J. Appl. Phys. 52, 7182\u20137190 (1981).","journal-title":"J. Appl. Phys."},{"key":"23546_CR71","doi-asserted-by":"publisher","first-page":"014101","DOI":"10.1063\/1.2408420","volume":"126","author":"G Bussi","year":"2007","unstructured":"Bussi, G., Donadio, D. & Parrinello, M. Canonical sampling through velocity rescaling. J. Chem. Phys. 126, 014101 (2007).","journal-title":"J. Chem. Phys."},{"key":"23546_CR72","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1021\/ct9005745","volume":"6","author":"GG Maisuradze","year":"2010","unstructured":"Maisuradze, G. G., Liwo, A. & Scheraga, H. A. Relation between free energy landscapes of proteins and dynamics. J. Chem. Theory Comput. 6, 583\u2013595 (2010).","journal-title":"J. Chem. Theory Comput."},{"key":"23546_CR73","doi-asserted-by":"publisher","first-page":"6281","DOI":"10.1021\/acs.jctc.1c00645","volume":"17","author":"MS Vald\u00e9s-Tresanco","year":"2021","unstructured":"Vald\u00e9s-Tresanco, M. S., Vald\u00e9s-Tresanco, M. E., Valiente, P. A., Moreno, E. & gmx_MMPBSA A new tool to perform End-State free energy calculations with GROMACS. J. Chem. Theory Comput. 17, 6281\u20136291 (2021).","journal-title":"J. Chem. Theory Comput."},{"key":"23546_CR74","doi-asserted-by":"publisher","first-page":"3314","DOI":"10.1021\/ct300418h","volume":"8","author":"BRI Miller","year":"2012","unstructured":"Miller, B. R. I. et al. MMPBSA.py: an efficient program for End-State free energy calculations. J. Chem. Theory Comput. 8, 3314\u20133321 (2012).","journal-title":"J. Chem. Theory Comput."},{"key":"23546_CR75","doi-asserted-by":"publisher","first-page":"1951","DOI":"10.1021\/ci500020m","volume":"54","author":"R Kumari","year":"2014","unstructured":"Kumari, R., Kumar, R., Lynn, A. & Open Source Drug Discovery Consortium. g_mmpbsa\u2013a GROMACS tool for high-throughput MM-PBSA calculations. J. Chem. Inf. Model. 54, 1951\u20131962 (2014).","journal-title":"J. Chem. Inf. Model."},{"key":"23546_CR76","doi-asserted-by":"publisher","first-page":"2062","DOI":"10.1093\/bioinformatics\/btt322","volume":"29","author":"A Lagunin","year":"2013","unstructured":"Lagunin, A., Ivanov, S., Rudik, A., Filimonov, D. & Poroikov, V. DIGEP-Pred: web service for in Silico prediction of drug-induced gene expression profiles based on structural formula. Bioinformatics 29, 2062\u20132063 (2013).","journal-title":"Bioinformatics"},{"key":"23546_CR77","doi-asserted-by":"publisher","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","volume":"51","author":"D Szklarczyk","year":"2023","unstructured":"Szklarczyk, D. et al. The STRING database in 2023: protein\u2013protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 51, D638\u2013D646 (2023).","journal-title":"Nucleic Acids Res."},{"key":"23546_CR78","doi-asserted-by":"publisher","unstructured":"Hagberg, A. A., Schult, D. A. & Swart, P. J. Exploring Network Structure, Dynamics, and Function Using NetworkXin 11\u201315 (Pasadena, 2008). https:\/\/doi.org\/10.25080\/TCWV9851","DOI":"10.25080\/TCWV9851"},{"key":"23546_CR79","unstructured":"Biovia, D. S. Discovery Studio Visualizer. San Diego. (2019)."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-23546-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-23546-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-23546-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T20:03:23Z","timestamp":1762977803000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-23546-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,12]]},"references-count":79,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["23546"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-23546-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,12]]},"assertion":[{"value":"7 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 November 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"39726"}}