{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T20:20:26Z","timestamp":1792182026094,"version":"4.4.0"},"reference-count":67,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Four sesquiterpenes, namely tomentosin, 11\u03b1,13-dihydrotomentosin, inuviscolide, and \u03b1-costic acid, were isolated from the aerial parts of the medicinal plant Dittrichia viscosa (L.) Greuter and evaluated for antiproliferative activity against HCT116 colorectal and A549 lung cancer cells. All compounds reduced cell viability in a concentration-dependent manner, with tomentosin and inuviscolide exhibiting the greatest activity among the tested compounds and IC50 values in the moderate micromolar range. Evaluation in non-malignant human neonatal dermal fibroblasts (HDFn) revealed compound- and cancer-type-dependent selectivity, with inuviscolide showing greater selectivity toward HCT116 cells and tomentosin showing moderate selectivity toward both cancer cell lines. In silico ADMET and DFT analyses characterized the predicted drug-likeness, pharmacokinetic, toxicity-related, and electronic properties of the compounds, particularly tomentosin and inuviscolide. Network pharmacology prioritized STAT3, ESR1, and PTGS2 as candidate hub targets associated with both cancer types, while enrichment analyses identified pathways related to tumor proliferation, inflammation, immune regulation, and cellular stress. Noncovalent molecular docking, 200 ns molecular dynamics simulations, and MM\/GBSA calculations supported possible modeled interactions of tomentosin and inuviscolide with these proteins, with tomentosin displaying the most favorable predicted binding profile. Covalent docking further identified structurally feasible STAT3 CYS687-linked poses with the two sesquiterpenes, although covalent adduct formation and direct target engagement remain to be experimentally validated. Overall, the integrated findings prioritize tomentosin and inuviscolide as D. viscosa-derived natural-product scaffolds with moderate antiproliferative activity for further structural optimization, selectivity assessment, and experimental mechanistic validation.<\/jats:p>","DOI":"10.3390\/ijms27157064","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T14:45:47Z","timestamp":1786027547000},"page":"7064","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["In Vitro and In Silico Insights into the Antiproliferative Activity of Sesquiterpenes from Dittrichia viscosa (L.) Greuter"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8318-3065","authenticated-orcid":false,"given":"Maria Michela","family":"Salvatore","sequence":"first","affiliation":[{"name":"Department of Veterinary Medicine and Animal Production, University of Naples Federico II, 80137 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0609-8902","authenticated-orcid":false,"given":"Marco","family":"Masi","sequence":"additional","affiliation":[{"name":"Department of Chemical Science, University of Naples Federico II, 80126 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Suleman","sequence":"additional","affiliation":[{"name":"Biomedical Research Center (BRC), QU Health, Qatar University, Doha P.O. Box 2713, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5214-9087","authenticated-orcid":false,"given":"Haritha","family":"Kalath","sequence":"additional","affiliation":[{"name":"Biomedical Research Center (BRC), QU Health, Qatar University, Doha P.O. Box 2713, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai M.","family":"Karousa","sequence":"additional","affiliation":[{"name":"Biomedical Research Center (BRC), QU Health, Qatar University, Doha P.O. Box 2713, Qatar"},{"name":"Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha P.O. Box 2713, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1596-5928","authenticated-orcid":false,"given":"Maha M.","family":"Ayoub","sequence":"additional","affiliation":[{"name":"Biomedical Research Center (BRC), QU Health, Qatar University, Doha P.O. Box 2713, Qatar"},{"name":"Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha P.O. Box 2713, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3524-7962","authenticated-orcid":false,"given":"Abdullah A.","family":"Shaito","sequence":"additional","affiliation":[{"name":"Biomedical Research Center (BRC), QU Health, Qatar University, Doha P.O. Box 2713, Qatar"},{"name":"Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha P.O. Box 2713, Qatar"},{"name":"College of Medicine, Qatar University, QU Health, Qatar University, Doha P.O. Box 2713, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8949-3654","authenticated-orcid":false,"given":"Anna","family":"Andolfi","sequence":"additional","affiliation":[{"name":"Department of Chemical Science, University of Naples Federico II, 80126 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Sladonja, B., Poljuha, D., Krapac, M., Uzelac, M., and Mikulic-Petkovsek, M. (2021). Dittrichia viscosa: Native-Non Native Invader. Diversity, 13.","DOI":"10.3390\/d13080380"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.jtcme.2024.03.012","article-title":"A Comprehensive Review on Ethnomedicinal Uses, Phytochemistry, Toxicology, and Pharmacological Activities of Dittrichia viscosa (L.) Greuter","volume":"14","author":"Jerada","year":"2024","journal-title":"J. Tradit. Complement. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Mrid, R.B., Bouchmaa, N., Kabach, I., Zouaoui, Z., Chtibi, H., El Maadoudi, M., Kounnoun, A., Cacciola, F., El Majdoub, Y.O., and Mondello, L. (2022). Dittrichia viscosa L. Leaves: A Valuable Source of Bioactive Compounds with Multiple Pharmacological Effects. Molecules, 27.","DOI":"10.3390\/molecules27072108"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"114211","DOI":"10.1016\/j.jep.2021.114211","article-title":"Evaluation of Cytotoxic and Antioxidant Potential of Dittrichia viscosa (L.) Greuter Used in Traditional Medicine","volume":"276","author":"Sevgi","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Anglana, C., Rojas, M., Girelli, C.R., Barozzi, F., Quiroz-Troncoso, J., Alegr\u00eda-Aravena, N., Montefusco, A., Durante, M., Fanizzi, F.P., and Ram\u00edrez-Castillejo, C. (2023). Methanolic Extracts of D. viscosa Specifically Affect the Cytoskeleton and Exert an Antiproliferative Effect on Human Colorectal Cancer Cell Lines, According to Their Proliferation Rate. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241914920"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4081253","DOI":"10.1155\/2019\/4081253","article-title":"Dittrichia viscosa L. Ethanolic Extract Based Ointment with Antiradical, Antioxidant, and Healing Wound Activities","volume":"2019","author":"Rhimi","year":"2019","journal-title":"BioMed Res. Int."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Grauso, L., Cesarano, G., Zotti, M., Ranesi, M., Sun, W., Bonanomi, G., and Lanzotti, V. (2020). Exploring Dittrichia viscosa (L.) Greuter Phytochemical Diversity to Explain Its Antimicrobial, Nematicidal and Insecticidal Activity, Springer.","DOI":"10.1007\/s11101-019-09607-1"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"105707","DOI":"10.1016\/j.fitote.2023.105707","article-title":"Exploring the Wound-Healing and Antimicrobial Potential of Dittrichia viscosa L. Lipidic Extract: Chemical Composition and in Vivo Evaluation","volume":"172","author":"Bentarhlia","year":"2024","journal-title":"Fitoterapia"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.indcrop.2018.01.032","article-title":"Dittrichia viscosa L. Leaves Lipid Extract: An Unexploited Source of Essential Fatty Acids and Tocopherols with Antifungal and Anti-Inflammatory Properties","volume":"113","author":"Rhimi","year":"2018","journal-title":"Ind. Crops Prod."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Segura-Navarro, M.J., Qu\u00edlez del Moral, J.F., Andr\u00e9s, M.F., Valc\u00e1rcel, F., Gonz\u00e1lez-Coloma, A., Molina Inzunza, D.O., and Barrero, A.F. (2025). Major Components of Dittrichia viscosa (Asteraceae) as a Source of New Pesticides. Molecules, 30.","DOI":"10.3390\/molecules30193950"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1038\/s40494-026-02436-4","article-title":"Screening of Dittrichia viscosa (L.) Greuter Metabolites as Potential Natural Biocides for Cultural Heritage Applications","volume":"14","author":"Morelli","year":"2026","journal-title":"npj Herit. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Lee, C.M., Lee, J., Nam, M.J., Choi, Y.S., and Park, S.H. (2019). Tomentosin Displays Anti-Carcinogenic Effect in Human Osteosarcoma MG-63 Cells via the Induction of Intracellular Reactive Oxygen Species. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20061508"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.bcp.2007.08.024","article-title":"Induction of G2\/M Arrest and Apoptosis by Sesquiterpene Lactones in Human Melanoma Cell Lines","volume":"75","author":"Rozenblat","year":"2008","journal-title":"Biochem. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Matos, M.S., Anast\u00e1cio, J.D., and Dos Santos, C.N. (2021). Sesquiterpene Lactones: Promising Natural Compounds to Fight Inflammation. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13070991"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"El Omari, N., El Menyiy, N., Zengin, G., Goh, B.H., Gallo, M., Montesano, D., Naviglio, D., and Bouyahya, A. (2021). Anticancer and Anti-Inflammatory Effects of Tomentosin: Cellular and Molecular Mechanisms. Separations, 8.","DOI":"10.3390\/separations8110207"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Migheli, R., Virdis, P., Galleri, G., Arru, C., Lostia, G., Coradduzza, D., Muroni, M.R., Pintore, G., Podda, L., and Fozza, C. (2022). Antineoplastic Properties by Proapoptotic Mechanisms Induction of Inula viscosa and Its Sesquiterpene Lactones Tomentosin and Inuviscolide. Biomedicines, 10.","DOI":"10.3390\/biomedicines10112739"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"12745","DOI":"10.1007\/s00210-025-04111-0","article-title":"A Sesquiterpene Lactone, Tomentosin, as a Novel Anticancer Agent: Orchestrating Apoptosis, Autophagy, and ER Stress in Colorectal Cancer","volume":"398","author":"Vural","year":"2025","journal-title":"Naunyn. Schmiedebergs. Arch. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6984","DOI":"10.1002\/anie.201202643","article-title":"Enantioselective and Collective Syntheses of Xanthanolides Involving a Controllable Dyotropic Rearrangement of cis-\u03b2-Lactones","volume":"51","author":"Ren","year":"2012","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Kebbi, S., Ciavatta, M.L., Mahmoud, A.M., Carbone, M., Ligresti, A., Seghiri, R., and Gavagnin, M. (2021). Sesquiterpene Lactones with the 12,8-Guaianolide Skeleton from Algerian Centaurea omphalotricha. Biomolecules, 11.","DOI":"10.3390\/biom11071053"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1021\/acs.jnatprod.5b00208","article-title":"Guaianolides and a Seco-Eudesmane from the Resinous Exudates of Cushion Bush (Leucophyta brownii) and Evaluation of Their Cytostatic and Anti-Inflammatory Activity","volume":"78","author":"Hyldgaard","year":"2015","journal-title":"J. Nat. Prod."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Vu, Q.V., Sayama, S., Ando, M., and Kataoka, T. (2024). Sesquiterpene lactones containing an \u03b1-methylene-\u03b3-lactone moiety selectively down-regulate the expression of tumor necrosis factor receptor 1 by promoting its ectodomain shedding in human lung adenocarcinoma A549 cells. Molecules, 29.","DOI":"10.3390\/molecules29081866"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1002\/ddr.430340203","article-title":"Some Practical Considerations and Applications of the National Cancer Institute In Vitro Anticancer Drug Discovery Screen","volume":"34","author":"Boyd","year":"1995","journal-title":"Drug Dev. Res."},{"key":"ref_23","first-page":"1","article-title":"Protocols for Screening Chemical Agents and Natural Products against Animal Tumors and Other Biological Systems","volume":"Volume 3","author":"Geran","year":"1972","journal-title":"Cancer Chemotherapy Reports"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1016\/j.apsb.2019.10.001","article-title":"Current Trends in Drug Metabolism and Pharmacokinetics","volume":"9","author":"Li","year":"2019","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1039\/C8MD00472B","article-title":"ADMET-Score\u2013a Comprehensive Scoring Function for Evaluation of Chemical Drug-Likeness","volume":"10","author":"Guan","year":"2019","journal-title":"Medchemcomm"},{"key":"ref_26","first-page":"17","article-title":"Protein-Protein Interaction Networks (PPI) and Complex Diseases","volume":"7","author":"Taghizadeh","year":"2014","journal-title":"Gastroenterol. Hepatol. Bed Bench"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.3892\/ijo.2012.1568","article-title":"STAT3 Inhibition, a Novel Approach to Enhancing Targeted Therapy in Human Cancers (Review)","volume":"41","author":"Wang","year":"2012","journal-title":"Int. J. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"988","DOI":"10.6026\/97320630008988","article-title":"Molecular Docking Studies on Inhibition of Stat3 Dimerization by Curcumin Natural Derivatives and Its Conjugates with Amino Acids","volume":"8","author":"Kumar","year":"2012","journal-title":"Bioinformation"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.ccell.2019.10.002","article-title":"A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo","volume":"36","author":"Bai","year":"2019","journal-title":"Cancer Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1016\/S0092-8674(00)81717-1","article-title":"The Structural Basis of Estrogen Receptor\/Coactivator Recognition and the Antagonism of This Interaction by Tamoxifen","volume":"95","author":"Shiau","year":"1998","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1107\/S2053230X16014230","article-title":"Crystal Structure of Rofecoxib Bound to Human Cyclooxygenase-2","volume":"72","author":"Orlando","year":"2016","journal-title":"Acta Crystallogr. Sect. F Struct. Biol. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Hawash, M., Jaradat, N., Abualhasan, M., \u015e\u00fck\u00fcro\u011flu, M.K., Qaoud, M.T., Kahraman, D.C., Daraghmeh, H., Maslamani, L., Sawafta, M., and Ratrout, A. (2023). Design, Synthesis, Molecular Docking Studies and Biological Evaluation of Thiazole Carboxamide Derivatives as COX Inhibitors. BMC Chem., 17.","DOI":"10.1186\/s13065-023-00924-3"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Le\u00e3o, R.P., Cruz, J.V., da Costa, G.V., Cruz, J.N., Ferreira, E.F.B., Silva, R.C., de Lima, L.R., Borges, R.S., Dos Santos, G.B., and Santos, C.B.R. (2020). Identification of New Rofecoxib-Based Cyclooxygenase-2 Inhibitors: A Bioinformatics Approach. Pharmaceuticals, 13.","DOI":"10.3390\/ph13090209"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1186\/s43088-022-00296-y","article-title":"Flavonoids as Dual Inhibitors of Cyclooxygenase-2 (COX-2) and 5-Lipoxygenase (5-LOX): Molecular Docking and in Vitro Studies","volume":"11","author":"Nyokat","year":"2022","journal-title":"Beni. Suef. Univ. J. Basic Appl. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"12780","DOI":"10.3390\/ijms140612780","article-title":"Sesquiterpenoids Lactones: Benefits to Plants and People","volume":"14","author":"Chadwick","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1021\/acs.jmedchem.6b00788","article-title":"Covalent Modifiers: A Chemical Perspective on the Reactivity of \u03b1,\u03b2-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions","volume":"60","author":"Jackson","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6679","DOI":"10.1073\/pnas.0408930102","article-title":"Molecular Dynamics and Protein Function","volume":"102","author":"Karplus","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"14123","DOI":"10.1038\/s41598-024-61439-y","article-title":"Identification of Potential Modulators for Human GPD1 by Docking-Based Virtual Screening, Molecular Dynamics Simulations, Binding Free Energy Calculations, and DeLA-Drug Analysis","volume":"14","author":"Hu","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Rampogu, S., Lee, G., Park, J.S., Lee, K.W., and Kim, M.O. (2022). Molecular Docking and Molecular Dynamics Simulations Discover Curcumin Analogue as a Plausible Dual Inhibitor for SARS-CoV-2. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031771"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Suleman, M., Moltrasio, C., Tricarico, P.M., Marzano, A.V., and Crovella, S. (2024). Natural Compounds Targeting Thymic Stromal Lymphopoietin (TSLP): A Promising Therapeutic Strategy for Atopic Dermatitis. Biomolecules, 14.","DOI":"10.3390\/biom14121521"},{"key":"ref_41","first-page":"1178228","article-title":"Molecular Dynamics Simulation of Ligands from Anredera cordifolia (Binahong) to the Main Protease (Mpro) of SARS-CoV-2","volume":"1","author":"Fatriansyah","year":"2022","journal-title":"J. Trop. Med."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Ghufran, M., Khan, H.A., Ullah, M., Ghufran, S., Ayaz, M., Siddiq, M., Shams, S., and Bungau, S. (2022). In Silico Strategies for Designing of Peptide Inhibitors of and Proliferation. Cancers, 14.","DOI":"10.3390\/cancers14194884"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Karousa, M.M., Kalath, H., Karam, L., Suleman, M., Ayoub, M.M., Fathima, A., Rocha, M.A.M., Mechmechani, S., Pinto, D.C.G.A., and Yassine, H.M. (2026). Chrysopogon zizanioides (Vetiver) Essential Oil from Qatar Targets AKT1 and STAT3 in Colorectal and Lung Cancer: GC-MS Profiling, In Vitro Antiproliferative Activity, and In Silico Analyses. Plants, 15.","DOI":"10.3390\/plants15050784"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Seglab, F., Abou Assali, M., AlYafei, T., Hassan, H., Pinto, D.C.G.A., Baydoun, S., Al Thani, A.A., and Shaito, A.A. (2024). Chemical Composition, Antioxidant Capacity, and Anticancerous Effects against Human Lung Cancer Cells of a Terpenoid-Rich Fraction of Inula viscosa. Biology, 13.","DOI":"10.20944\/preprints202407.0755.v1"},{"key":"ref_45","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_46","doi-asserted-by":"crossref","first-page":"4066","DOI":"10.1021\/acs.jmedchem.5b00104","article-title":"PkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures","volume":"58","author":"Pires","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"W357","DOI":"10.1093\/nar\/gkz382","article-title":"SwissTargetPrediction: 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_48","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1080\/1062936X.2015.1078407","article-title":"PASS Targets: Ligand-Based Multi-Target Computational System Based on a Public Data and Na\u00efve Bayes Approach","volume":"26","author":"Pogodin","year":"2015","journal-title":"SAR QSAR Environ. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"D605","DOI":"10.1093\/nar\/gkaa1074","article-title":"The STRING Database in 2021: Customizable Protein\u2013Protein Networks, and Functional Characterization of User-Uploaded Gene\/Measurement Sets","volume":"49","author":"Szklarczyk","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1021\/acs.jproteome.2c00651","article-title":"Cytoscape StringApp 2.0: Analysis and Visualization of Heterogeneous Biological Networks","volume":"22","author":"Doncheva","year":"2023","journal-title":"J. Proteome Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1093\/bioinformatics\/btt138","article-title":"Cytoscape App Store","volume":"29","author":"Lotia","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Chin, C.H., Chen, S.H., Wu, H.H., Ho, C.W., Ko, M.T., and Lin, C.Y. (2014). CytoHubba: Identifying Hub Objects and Sub-Networks from Complex Interactome. BMC Syst. Biol., 8.","DOI":"10.1186\/1752-0509-8-S4-S11"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"D545","DOI":"10.1093\/nar\/gkaa970","article-title":"KEGG: Integrating Viruses and Cellular Organisms","volume":"49","author":"Kanehisa","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1093\/bioinformatics\/btz931","article-title":"ShinyGO: A Graphical Gene-Set Enrichment Tool for Animals and Plants","volume":"36","author":"Ge","year":"2020","journal-title":"Bioinformatics"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.1093\/bioinformatics\/btt285","article-title":"Pathview: An R\/Bioconductor Package for Pathway-Based Data Integration and Visualization","volume":"29","author":"Luo","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_56","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_57","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_58","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1038\/s41577-020-00473-z","article-title":"NOD-like Receptor-Mediated Plant Immunity: From Structure to Cell Death","volume":"21","author":"Saur","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1002\/jcc.20290","article-title":"The Amber Biomolecular Simulation Programs","volume":"26","author":"Case","year":"2005","journal-title":"J. Comput. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1002\/wcms.1121","article-title":"An Overview of the Amber Biomolecular Simulation Package","volume":"3","author":"Case","year":"2013","journal-title":"Wiley Interdiscip. Rev. Comput. Mol. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"10913","DOI":"10.1063\/1.1324708","article-title":"Efficient Particle-Mesh Ewald Based Approach to Fixed and Induced Dipolar Interactions","volume":"113","author":"Toukmaji","year":"2000","journal-title":"J. Chem. Phys."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1021\/ct200909j","article-title":"Routine Microsecond Molecular Dynamics Simulations with AMBER on GPUs. 2. Explicit Solvent Particle Mesh Ewald","volume":"8","author":"Williamson","year":"2012","journal-title":"J. Chem. Theory Comput."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3084","DOI":"10.1021\/ct400341p","article-title":"PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data","volume":"9","author":"Roe","year":"2013","journal-title":"J. Chem. Theory Comput."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1006\/jmbi.1994.1017","article-title":"Significance of Root-Mean-Square Deviation in Comparing Three-Dimensional Structures of Globular Proteins","volume":"235","author":"Maiorov","year":"1994","journal-title":"J. Mol. Biol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2740","DOI":"10.1073\/pnas.73.8.2740","article-title":"Thermodynamic Fluctuations in Protein Molecules","volume":"73","author":"Cooper","year":"1976","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1517\/17460441.2015.1032936","article-title":"The MM\/PBSA and MM\/GBSA Methods to Estimate Ligand-Binding Affinities","volume":"10","author":"Genheden","year":"2015","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"14450","DOI":"10.1039\/C7CP07623A","article-title":"Assessing the Performance of MM\/PBSA and MM\/GBSA Methods. 7. Entropy Effects on the Performance of End-Point Binding Free Energy Calculation Approaches","volume":"20","author":"Sun","year":"2018","journal-title":"Phys. Chem. Chem. Phys."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/7064\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T14:46:40Z","timestamp":1786027600000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/7064"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,6]]},"references-count":67,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27157064"],"URL":"https:\/\/doi.org\/10.3390\/ijms27157064","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,6]]}}}