{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T05:04:26Z","timestamp":1779771866676,"version":"3.53.1"},"reference-count":72,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Triple-negative breast cancer (TNBC) is a clinically aggressive malignancy with extremely limited effective targeted therapies. Natural products are promising alternatives for anticancer drug discovery, whereas integrated computational approaches serve as efficient tools for novel lead identification. Herein, four novel spiro-polycyclic sesquiterpene [4+2] trimers (Inubritantrimers A\u2013D) and eight synthetic derivatives from Inula britannica L. were investigated via DFT calculations at the \u03c9B97xD\/6-311++G(2d,p) level (for geometric, electronic, spectral, and reactivity parameters), network pharmacology, molecular docking against seven core breast cancer-related targets, 500 ns all-atom molecular dynamics (MD) simulation, and MM\/PBSA analysis. The results showed that the endo-type cycloaddition products had superior structural stability, with all reactions thermodynamically spontaneous (\u0394G &lt; 0). Compound 11 exhibited the most potent and balanced binding activity, with a docking free energy of \u221213.45 kcal\/mol to MTOR; MD and MM\/PBSA confirmed stable complex formation (total binding free energy \u221221.13 kcal\/mol), driven predominantly by hydrophobic interactions. This study first established a comprehensive stereochemistry\u2013electronic structure\u2013property\u2013activity relationship for this rare sesquiterpene trimer class and identified compound 11 as a promising MTOR-targeted TNBC lead. It provided a theoretical basis for developing high-efficiency, low-toxicity natural anticancer agents.<\/jats:p>","DOI":"10.3390\/molecules31101759","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T14:12:54Z","timestamp":1779286374000},"page":"1759","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Computational Investigation of Four Sesquiterpene [4+2] Trimers, Inubritantrimers A\u2013D, and Their Synthetic Intermediates Isolated from Inula britannica L."],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5785-796X","authenticated-orcid":false,"given":"Xiaoyun","family":"Xia","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiandong","family":"Du","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhifeng","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sisi","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2466-5704","authenticated-orcid":false,"given":"Chaojie","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1360\/SSC-2024-0272","article-title":"Research progress on the application of terpenoid resources in the total synthesis of natural products","volume":"55","author":"Li","year":"2025","journal-title":"Sci. Sin. Chim."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4779","DOI":"10.1021\/cr040632u","article-title":"Recent advances in natural product synthesis by using intramolecular Diels\u2212Alder reactions","volume":"105","author":"Takao","year":"2005","journal-title":"Chem. Rev."},{"key":"ref_3","first-page":"461","article-title":"Application of ascending, lowering, floating and sinking medicinal properties of the flos inulae in classical formulae","volume":"40","author":"Ma","year":"2023","journal-title":"Tianjin J. Trad. Chin. Med."},{"key":"ref_4","first-page":"2591","article-title":"Research progress on chemical compositions and pharmacological effects of Inulae Flos","volume":"45","author":"Zheng","year":"2022","journal-title":"Drug Eval. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1007\/s00011-021-01538-y","article-title":"Japonicone A and related dimeric sesquiterpene lactones: Molecular targets and mechanisms of anticancer activity","volume":"71","author":"Bailly","year":"2022","journal-title":"Inflamm. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"112622","DOI":"10.1016\/j.ejmech.2020.112622","article-title":"Natural sesquiterpenoid oligomers: A chemical perspective","volume":"203","author":"Zhao","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1039\/c2ra01014c","article-title":"Lineariifolianoids A\u2013D, rare unsymmetrical sesquiterpenoid dimers comprised of xanthane and guaiane framework units from Inula lineariifolia","volume":"2","author":"Qin","year":"2012","journal-title":"RSC Adv."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4473","DOI":"10.1021\/acs.joc.8b03284","article-title":"Heliaquanoids A\u2013E, five sesquiterpenoid dimers from Inula helianthus-aquatica","volume":"84","author":"Zheng","year":"2019","journal-title":"J. Org. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.fitote.2015.01.011","article-title":"Cytotoxic sesquiterpene lactone dimers isolated from Inula japonica","volume":"101","author":"Xu","year":"2015","journal-title":"Fitoterapia"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1080\/10286020.2021.1923012","article-title":"Anti-inflammatory sesquiterpene dimers and diterpenes from the aerial part of Inula japonica","volume":"24","author":"Wu","year":"2022","journal-title":"J. Asian Nat. Prod. Res."},{"key":"ref_11","first-page":"401","article-title":"Novel natural product therapeutics targeting both inflammation and cancer","volume":"15","author":"Qin","year":"2017","journal-title":"Chin. J. Nat. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.phytochem.2018.07.008","article-title":"Dimeric- and trimeric sesquiterpenes from the flower of Inula japonica","volume":"155","author":"Jin","year":"2018","journal-title":"Phytochemistry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"113951","DOI":"10.1016\/j.phytochem.2023.113951","article-title":"Dimerized sesquiterpenoid [4 + 2] adducts with ferroptosis-promoting activity from Inula britannica Linn","volume":"218","author":"Guo","year":"2024","journal-title":"Phytochemistry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5029","DOI":"10.1021\/acs.joc.4c00248","article-title":"Inubritantrimers A\u2013D: Trimerized sesquiterpenoid [4 + 2] adducts featuring a distinctive spiro-polycyclic scaffold from Inula britannica","volume":"89","author":"Guo","year":"2024","journal-title":"J. Org. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Wei, J. (2007). Product Engineering: Molecular Structure and Properties, Oxford University Press.","DOI":"10.1093\/oso\/9780195159172.001.0001"},{"key":"ref_16","first-page":"1519","article-title":"A preliminary investigation on anti-tumor structure-activity relationship of lanostane triterpenes from Ganoderma spp.","volume":"41","author":"Yang","year":"2022","journal-title":"Mycosystema"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"7537","DOI":"10.1039\/D5SC00988J","article-title":"Adaptive nitrogen-containing buckybowl: A versatile receptor for curved and planar aromatic molecules","volume":"16","author":"Chen","year":"2025","journal-title":"Chem. Sci."},{"key":"ref_18","first-page":"101","article-title":"Current situation and prospect of pyrolysis analysis technology of organic wastes","volume":"37","author":"Zhu","year":"2023","journal-title":"Chin. Plast."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"9483","DOI":"10.1021\/ja970112z","article-title":"Computed 13C NMR chemical shifts via empirically scaled GIAO shieldings and molecular mechanics geometries. conformation and configuration from 13C shifts","volume":"119","author":"Forsyth","year":"1997","journal-title":"J. Am. Chem. Soc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1016\/j.bmcl.2008.12.043","article-title":"Japonicones A\u2013D, bioactive dimeric sesquiterpenes from Inula japonica Thunb","volume":"19","author":"Qin","year":"2009","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1038\/s41557-020-0467-7","article-title":"FAD-dependent enzyme-catalysed intermolecular [4+2] cycloaddition in natural product biosynthesis","volume":"12","author":"Gao","year":"2020","journal-title":"Nat. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/s11224-005-2831-z","article-title":"Theoretical and experimental study on 3-Phenyl-5-Phenylazo-3H-[1,3,4] Thiadiazole-2-Thione","volume":"16","author":"Jian","year":"2005","journal-title":"Struct. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"16502","DOI":"10.1021\/jp960976r","article-title":"Harmonic vibrational frequencies:\u2009 An evaluation of Hartree\u2212Fock, M\u00f8ller\u2212Plesset, quadratic configuration interaction, density functional theory, and semiempirical scale factors","volume":"100","author":"Scott","year":"1996","journal-title":"J. Phys. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1007\/s11224-012-0112-1","article-title":"Synthesis, molecular structure, and spectral analyses of ethyl-4-[(2,4-dinitrophenyl)-hydrazonomethyl]-3,5-dimethyl-1H-pyrrole-2-carboxylate","volume":"24","author":"Singh","year":"2013","journal-title":"Struct. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1002\/crat.201100481","article-title":"Substituent and solvent effects on UV-visible absorption spectra of liquid crystalline disubstituted biphenylcyclohexane derivatives-a computational approach","volume":"47","author":"Ojha","year":"2012","journal-title":"Cryst. Res. Technol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"184308","DOI":"10.1063\/1.4874267","article-title":"Analysis of nonlinear optical properties in donor-acceptor materials","volume":"140","author":"Day","year":"2014","journal-title":"J. Chem. Phys."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"10826","DOI":"10.1039\/C9RA10290F","article-title":"Synthesis and application of coumarin fluorescence probes","volume":"10","author":"Sun","year":"2020","journal-title":"RSC Adv."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8578","DOI":"10.1002\/chem.201406597","article-title":"What makes a strong organic electron donor (or Acceptor)?","volume":"21","author":"Eberle","year":"2015","journal-title":"Chemistry"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1002\/anie.198208013","article-title":"The role of frontier orbitals in chemical reactions (Nobel Lecture)","volume":"21","author":"Fukui","year":"1982","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2194","DOI":"10.1039\/c2py20957h","article-title":"Self-healing polymers based on thermally reversible Diels-Alder chemistry","volume":"4","author":"Liu","year":"2013","journal-title":"Polym. Chem."},{"key":"ref_31","first-page":"509","article-title":"Functional site prediction of BRCT domain containing phosphate binding pocket","volume":"32","author":"Sheng","year":"2011","journal-title":"Zool. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"165112","DOI":"10.1103\/PhysRevB.88.165112","article-title":"Constrained-DFT method for accurate energy-level alignment of metal\/molecule interfaces","volume":"88","author":"Souza","year":"2013","journal-title":"Phys. Rev. B"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"20382","DOI":"10.1021\/acsomega.0c02354","article-title":"Density functional theory studies on the antioxidant mechanism and electronic properties of some bioactive marine meroterpenoids: Sargahydroquionic acid and sargachromanol","volume":"5","author":"Farrokhnia","year":"2020","journal-title":"ACS Omega"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Sakata, K., Go, Y., and Yoshikawa, T. (2025). Reactivity and stereoselectivity in the inverse-electron-demand Diels-Alder reaction of 1-Aza-1,3-Butadiene. Molecules, 30.","DOI":"10.3390\/molecules30193861"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1139\/cjc-2017-0389","article-title":"Dipole-induced effects on charge transfer and charge transport. Why do molecular electrets matter?","volume":"96","author":"Derr","year":"2018","journal-title":"Can. J. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"B110","DOI":"10.1115\/1.1421125","article-title":"Chemical thermodynamics: Principles and applications","volume":"54","author":"Ott","year":"2001","journal-title":"Appl. Mech. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"082503","DOI":"10.1063\/5.0216272","article-title":"A comprehensive electron wavefunction analysis toolbox for chemists, Multiwfn","volume":"161","author":"Lu","year":"2024","journal-title":"J. Chem. Phys."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.jssc.2014.08.004","article-title":"Atomic charges for modeling metal\u2013organic frameworks: Why and how","volume":"223","author":"Hamad","year":"2015","journal-title":"J. Solid State Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"W422","DOI":"10.1093\/nar\/gkae236","article-title":"ADMETlab 3.0: An updated comprehensive online ADMET prediction platform enhanced with broader coverage, improved performance, API functionality and decision support","volume":"52","author":"Fu","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Zhan, X., Li, H., Jin, J., Ju, X., Gao, J., Chen, X., Yuan, F., Gu, J., Xu, D., and Ju, G. (2024). Network pharmacology and experimental validation to explore the role and potential mechanism of Liuwei Dihuang Decoction in prostate cancer. BMC Complement. Med. Ther., 24.","DOI":"10.1186\/s12906-024-04572-5"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Xie, R., Li, B., Jia, L., and Li, Y. (2022). Identification of core genes and pathways in melanoma metastasis via bioinformatics analysis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23020794"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"bbab108","DOI":"10.1093\/bib\/bbab108","article-title":"Venn diagrams in bioinformatics","volume":"22","author":"Jia","year":"2021","journal-title":"Brief. Bioinform."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"W216","DOI":"10.1093\/nar\/gkac194","article-title":"DAVID: A web server for functional enrichment analysis and functional annotation of gene lists (2021 update)","volume":"50","author":"Sherman","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1.30.31","DOI":"10.1002\/cpbi.5","article-title":"The GeneCards suite: From gene data mining to disease genome sequence analyses","volume":"54","author":"Stelzer","year":"2016","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"109750","DOI":"10.1016\/j.isci.2024.109750","article-title":"Bispecific radioimmuno conjugates exploit receptor heterogeneity for positron emission tomography of tumors expressing HER2 and\/or EGFR","volume":"27","author":"Kwon","year":"2024","journal-title":"iScience"},{"key":"ref_46","first-page":"649","article-title":"Activation of Keap1\/Nrf2 signaling pathway by nuclear epidermal growth factor receptor in cancer cells","volume":"6","author":"Huo","year":"2014","journal-title":"Am. J. Transl. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4936","DOI":"10.1021\/jm300354j","article-title":"Structure-based design of novel inhibitors of the MDM2\u2013p53 interaction","volume":"55","author":"Rew","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Hacholli, V.B., R., S.M., H., P.B., M., L., S., P., Kumar, A., Szeleszczuk, \u0141., and Gackowski, M. (2025). Coumarin derivatives as anticancer agents: Mechanistic landscape with an emphasis on breast cancer. Molecules, 30.","DOI":"10.3390\/molecules30214167"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Mioc, M., Gruin, S., Gogulescu, A., B\u0103tr\u00eena, O., Jorgovan, M., Mara, B.-I., and \u0218oica, C. (2025). Targeting anti-apoptotic Bcl-2 proteins with triterpene-heterocyclic derivatives: A combined dual docking and molecular dynamics Study. Molecules, 30.","DOI":"10.3390\/molecules30193919"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Jang, D.I., Lee, A.H., Shin, H.Y., Song, H.R., Park, J.H., Kang, T.B., Lee, S.R., and Yang, S.H. (2021). The role of tumor necrosis factor alpha (TNF-\u03b1) in autoimmune disease and current TNF-\u03b1 inhibitors in therapeutics. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052719"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Lestari, B., Utomo, R.Y., Rahman, F.A., Putri, D.D.P., Zulfin, U.M., Suenaga, Y., Meiyanto, E., and Hippo, Y. (2025). Discovery of pyroptosis-inducing natural products in neuroblastomas: Computational studies with experimental validation. BMC Complement. Med. Ther., 25.","DOI":"10.1186\/s12906-025-05004-8"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.bbrc.2013.10.057","article-title":"CB1 and CB2 receptors are novel molecular targets for Tamoxifen and 4OH-Tamoxifen","volume":"441","author":"Prather","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_53","first-page":"1143","article-title":"Rapamycin effects on mTOR signaling in benign, premalignant and malignant human breast epithelial cells","volume":"29","author":"Kim","year":"2009","journal-title":"Anticancer Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1186\/s13058-019-1154-8","article-title":"Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and\/or PTEN loss\/PTEN mutation","volume":"21","author":"Xing","year":"2019","journal-title":"Breast Cancer Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/cdd.2017.161","article-title":"The BCL-2 arbiters of apoptosis and their growing role as cancer targets","volume":"25","author":"Adams","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2744","DOI":"10.1002\/cmdc.202100332","article-title":"Chemical and structural strategies to selectively target mTOR kinase","volume":"16","author":"Borsari","year":"2021","journal-title":"Chem. Med. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"10068","DOI":"10.1021\/jp904674x","article-title":"Net Electrophilicity","volume":"113","author":"Chattaraj","year":"2009","journal-title":"J. Phys. Chem. A"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1922","DOI":"10.1021\/ja983494x","article-title":"Electrophilicity Index","volume":"121","author":"Parr","year":"1999","journal-title":"J. Am. Chem. Soc."},{"key":"ref_59","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Petersson, G.A., and Nakatsuji, H. (2016). Gaussian 16, Gaussian Inc.. Volume Revision B.01."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1002\/jcc.22885","article-title":"Multiwfn: A multifunctional wavefunction analyzer","volume":"33","author":"Lu","year":"2012","journal-title":"J. Comput. Chem."},{"key":"ref_61","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_62","doi-asserted-by":"crossref","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"W357","DOI":"10.1093\/nar\/gkz382","article-title":"Swiss Target Prediction: Updated data and new features for efficient prediction of protein targets of small molecules","volume":"47","author":"Daina","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"D480","DOI":"10.1093\/nar\/gkaa1100","article-title":"UniProt: The universal protein knowledgebase in 2021","volume":"49","author":"Consortium","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1093\/nar\/gkac1247","article-title":"Annotation of uORFs in the OMIM genes allows to reveal pathogenic variants in 5\u2032UTRs","volume":"51","author":"Filatova","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"baae122","DOI":"10.1093\/database\/baae122","article-title":"DisGeNet: A disease-centric interaction database among diseases and various associated genes","volume":"2025","author":"Hu","year":"2025","journal-title":"Database"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"W593","DOI":"10.1093\/nar\/gkac389","article-title":"PrankWeb 3: Accelerated ligand-binding site predictions for experimental and modelled protein structures","volume":"50","author":"Jakubec","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_68","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_69","doi-asserted-by":"crossref","first-page":"W463","DOI":"10.1093\/nar\/gkaf361","article-title":"PLIP 2025: Introducing protein\u2013protein interactions to the protein\u2013ligand interaction profiler","volume":"53","author":"Schake","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e1298","DOI":"10.1002\/wcms.1298","article-title":"Using PyMOL as a platform for computational drug design","volume":"7","author":"Yuan","year":"2017","journal-title":"WIREs Comput. Mol. Sci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2778","DOI":"10.1021\/ci200227u","article-title":"LigPlot+: Multiple ligand\u2013protein interaction diagrams for drug discovery","volume":"51","author":"Laskowski","year":"2011","journal-title":"J. Chem. Inf. Model."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1002\/jcc.20291","article-title":"GROMACS: Fast, flexible, and free","volume":"26","author":"Lindahl","year":"2005","journal-title":"J. Comput. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/10\/1759\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T04:30:00Z","timestamp":1779769800000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/10\/1759"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,20]]},"references-count":72,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["molecules31101759"],"URL":"https:\/\/doi.org\/10.3390\/molecules31101759","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,20]]}}}