{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:27:33Z","timestamp":1760146053895,"version":"build-2065373602"},"reference-count":68,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2024,10,1]],"date-time":"2024-10-01T00:00:00Z","timestamp":1727740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"German Federal Ministry of Education and Research (BMBF)","award":["Med-MelAutim 01ZX2205B"],"award-info":[{"award-number":["Med-MelAutim 01ZX2205B"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The landscape of clinical management for metastatic melanoma (MM) and other solid tumors has been modernized by the advent of immune checkpoint inhibitors (ICI), including programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors. While these agents demonstrate efficacy in suppressing tumor growth, they also lead to immune-related adverse events (irAEs), resulting in the exacerbation of autoimmune diseases such as rheumatoid arthritis (RA), ulcerative colitis (UC), and Crohn\u2019s disease (CD). The immune checkpoint inhibitors offer promising advancements in the treatment of melanoma and other cancers, but they also present significant challenges related to irAEs and autoimmune diseases. Ongoing research is crucial to better understand these challenges and develop strategies for mitigating adverse effects while maximizing therapeutic benefits. In this manuscript, we addressed this challenge using network-based approaches by constructing and analyzing the molecular and signaling networks associated with tumor-immune crosstalk. Our analysis revealed that IL6 is the key regulator responsible for irAEs during ICI therapies. Furthermore, we conducted an integrative network and molecular-level analysis, including virtual screening, of drug libraries, such as the Collection of Open Natural Products (COCONUT) and the Zinc15 FDA-approved library, to identify potential IL6 inhibitors. Subsequently, the compound amprenavir was identified as the best molecule that may disrupt essential interactions between IL6 and IL6R, which are responsible for initiating the signaling cascades underlying irAEs in ICI therapies.<\/jats:p>","DOI":"10.3390\/ijms251910600","type":"journal-article","created":{"date-parts":[[2024,10,1]],"date-time":"2024-10-01T11:08:47Z","timestamp":1727780927000},"page":"10600","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Regulatory Role of IL6 in Immune-Related Adverse Events during Checkpoint Inhibitor Treatment in Melanoma"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-8789-615X","authenticated-orcid":false,"given":"Krishna P.","family":"Singh","sequence":"first","affiliation":[{"name":"Department of Systems Biology & Bioinformatics, University of Rostock, 18051 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3406-7587","authenticated-orcid":false,"given":"Anuj","family":"Singh","sequence":"additional","affiliation":[{"name":"Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6105-2937","authenticated-orcid":false,"given":"Olaf","family":"Wolkenhauer","sequence":"additional","affiliation":[{"name":"Department of Systems Biology & Bioinformatics, University of Rostock, 18051 Rostock, Germany"},{"name":"Department of Biomedical Engineering & Bioinformatics, Chhattisgarh Swami Vivekananda Technical University, Bhilai 491107, India"},{"name":"Leibniz Institute for Food Systems Biology, Technical University of Munich, 85354 Freising, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3470-3260","authenticated-orcid":false,"given":"Shailendra Kumar","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Systems Biology & Bioinformatics, University of Rostock, 18051 Rostock, Germany"},{"name":"Department of Biomedical Engineering & Bioinformatics, Chhattisgarh Swami Vivekananda Technical University, Bhilai 491107, India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.pathol.2022.11.006","article-title":"Metastatic melanoma and rare melanoma variants: A review","volume":"55","author":"Lowe","year":"2023","journal-title":"Pathology"},{"key":"ref_2","unstructured":"Rausch, M.P., and Hastings, K.T. (2017). Immune Checkpoint Inhibitors in the Treatment of Melanoma: From Basic Science to Clinical Application. Cutaneous Melanoma: Etiology and Therapy, AU."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Shah, V., Panchal, V., Shah, A., Vyas, B., Agrawal, S., and Bharadwaj, S. (2024). Immune checkpoint inhibitors in metastatic melanoma therapy (Review). Med. Int., 4.","DOI":"10.3892\/mi.2024.137"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3044","DOI":"10.3390\/curroncol29050247","article-title":"Immune Checkpoint Inhibitors in Cancer Therapy","volume":"29","author":"Shiravand","year":"2022","journal-title":"Curr. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1097\/CMR.0000000000000573","article-title":"Melanoma and autoimmunity: Spontaneous regressions as a possible model for new therapeutic approaches","volume":"29","author":"Motofei","year":"2019","journal-title":"Melanoma Res."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Ibis, B., Aliazis, K., Cao, C., Yenyuwadee, S., and Boussiotis, V.A. (2023). Immune-related adverse effects of checkpoint immunotherapy and implications for the treatment of patients with cancer and autoimmune diseases. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1197364"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Darvin, P., Toor, S.M., Sasidharan Nair, V., and Elkord, E. (2018). Immune checkpoint inhibitors: Recent progress and potential biomarkers. Exp. Mol. Med., 50.","DOI":"10.1038\/s12276-018-0191-1"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.semcancer.2019.06.012","article-title":"Autoimmunity, Checkpoint Inhibitor Therapy and Immune-related Adverse Events: A Review","volume":"64","author":"Khan","year":"2020","journal-title":"Semin. Cancer Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1038\/s41416-021-01390-1","article-title":"Checkpoint blocker induced autoimmunity as an indicator for tumour efficacy in melanoma","volume":"126","author":"Hassel","year":"2021","journal-title":"Br. J. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Portenkirchner, C., Kienle, P., and Horisberger, K. (2021). Checkpoint inhibitor-induced colitis\u2014A clinical overview of incidence, prognostic implications and extension of current treatment options. Pharmaceuticals, 14.","DOI":"10.3390\/ph14040367"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1111\/apt.16210","article-title":"Immune-mediated disease and Risk of Crohn\u2019s Disease or Ulcerative Colitis: A Prospective Cohort Study","volume":"53","author":"Lo","year":"2021","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1097\/BOR.0000000000000701","article-title":"Treatment of immune checkpoint inhibitor-induced inflammatory arthritis","volume":"32","author":"Jeurling","year":"2020","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Bader, G.D., and Hogue, C.W.V. (2003). An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinform., 4.","DOI":"10.1186\/1471-2105-4-2"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Iwaszko, M., Bia\u0142y, S., and Bogunia-Kubik, K. (2021). Significance of Interleukin (IL)-4 and IL-13 in Inflammatory Arthritis. Cells, 10.","DOI":"10.3390\/cells10113000"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Eddy, K., Shah, R., and Chen, S. (2021). Decoding Melanoma Development and Progression: Identification of Therapeutic Vulnerabilities. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.626129"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Napolitano, M., di Vico, F., Ruggiero, A., Fabbrocini, G., and Patruno, C. (2023). The hidden sentinel of the skin: An overview on the role of interleukin-13 in atopic dermatitis. Front. Med., 10.","DOI":"10.3389\/fmed.2023.1165098"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1097\/CMR.0b013e3283543d72","article-title":"Interleukin-6 and melanoma","volume":"22","author":"Hoejberg","year":"2012","journal-title":"Melanoma Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1081\/CNV-100102550","article-title":"Comparison of serum interleukin-10 (IL-10) levels between normal volunteers and patients with advanced melanoma","volume":"19","author":"Nemunaitis","year":"2001","journal-title":"Cancer Investig."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Tanaka, T., Narazaki, M., and Kishimoto, T. (2014). IL-6 in inflammation, immunity, and disease. Cold Spring Harb. Perspect. Biol., 6.","DOI":"10.1101\/cshperspect.a016295"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Voronov, E., Carmi, Y., and Apte, R.N. (2014). The role IL-1 in tumor-mediated angiogenesis. Front. Physiol., 5.","DOI":"10.3389\/fphys.2014.00114"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/S1359-6101(02)00021-7","article-title":"Roles of IL-1 in the development of rheumatoid arthritis: Consideration from mouse models","volume":"13","author":"Iwakura","year":"2002","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Silva, F.A.R., Rodrigues, B.L., Ayrizono, M.D.L.S., and Leal, R.F. (2016). The Immunological Basis of Inflammatory Bowel Disease. Gastroenterol. Res. Pract., 2016.","DOI":"10.1155\/2016\/2097274"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1046\/j.1523-1747.2000.00068.x","article-title":"Matrix metalloproteinases in human melanoma","volume":"115","author":"Hofmann","year":"2000","journal-title":"J. Investig. Dermatol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Cabral-Pacheco, G.A., Garza-Veloz, I., la Rosa, C.C.D., Ramirez-Acu\u00f1a, J.M., Perez-Romero, B.A., Guerrero-Rodriguez, J.F., Martinez-Avila, N., and Martinez-Fierro, M.L. (2020). The Roles of Matrix Metalloproteinases and Their Inhibitors in Human Diseases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249739"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1159\/000336995","article-title":"The impact of matrix metalloproteinases and their tissue inhibitors in inflammatory bowel diseases","volume":"30","author":"Lakatos","year":"2012","journal-title":"Dig. Dis."},{"key":"ref_26","first-page":"1997","article-title":"ERK\/MAPK signalling pathway and tumorigenesis","volume":"19","author":"Guo","year":"2020","journal-title":"Exp. Ther. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/sj.cr.7290105","article-title":"MAPK signal pathways in the regulation of cell proliferation in mammalian cells","volume":"12","author":"Wei","year":"2002","journal-title":"Cell Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Skytthe, M.K., Graversen, J.H., and Moestrup, S.K. (2020). Targeting of CD163+ Macrophages in Inflammatory and Malignant Diseases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21155497"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2352","DOI":"10.1089\/ars.2012.4834","article-title":"CD163 and inflammation: Biological, diagnostic, and therapeutic aspects","volume":"18","author":"Etzerodt","year":"2013","journal-title":"Antioxid. Redox Signal."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3166","DOI":"10.1038\/s41388-018-0209-0","article-title":"Collagen abundance controls melanoma phenotypes through lineage-specific microenvironment sensing","volume":"37","author":"Miskolczi","year":"2018","journal-title":"Oncogene"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1002\/ijc.23147","article-title":"Type I collagen expression contributes to angiogenesis and the development of deeply invasive cutaneous melanoma","volume":"122","author":"Rijntjes","year":"2008","journal-title":"Int. J. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Gencoglu, H., Orhan, C., Sahin, E., and Sahin, K. (2020). Undenatured Type II Collagen (UC-II) in Joint Health and Disease: A Review on the Current Knowledge of Companion Animals. Animals, 10.","DOI":"10.3390\/ani10040697"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Jarlborg, M., and Gabay, C. (2022). Systemic effects of IL-6 blockade in rheumatoid arthritis beyond the joints. Cytokine, 149.","DOI":"10.1016\/j.cyto.2021.155742"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Ra\u0161kov\u00e1, M., Lacina, L., Kej\u00edk, Z., Venhauerov\u00e1, A., Skali\u010dkov\u00e1, M., Kol\u00e1\u0159, M., Jakubek, M., Rosel, D., Smetana, K., and Br\u00e1bek, J. (2022). The Role of IL-6 in Cancer Cell Invasiveness and Metastasis-Overview and Therapeutic Opportunities. Cells, 11.","DOI":"10.3390\/cells11223698"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s12079-022-00695-x","article-title":"Role of interleukin-6-mediated inflammation in the pathogenesis of inflammatory bowel disease: Focus on the available therapeutic approaches and gut microbiome","volume":"17","author":"Shahini","year":"2023","journal-title":"J. Cell Commun. Signal."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4073","DOI":"10.1200\/JCO.21.01440","article-title":"Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update","volume":"39","author":"Schneider","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.jdermsci.2016.12.019","article-title":"Serum level of interleukin-6 is increased in nivolumab-associated psoriasiform dermatitis and tumor necrosis factor-\u03b1 is a biomarker of nivolumab recativity","volume":"86","author":"Tanaka","year":"2017","journal-title":"J. Dermatol. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/j.ccell.2022.04.004","article-title":"Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity","volume":"40","author":"Hailemichael","year":"2022","journal-title":"Cancer Cell"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Lei, Y., Li, X., Huang, Q., Zheng, X., and Liu, M. (2021). Progress and Challenges of Predictive Biomarkers for Immune Checkpoint Blockade. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.617335"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"281","DOI":"10.5114\/ceji.2018.80047","article-title":"Correlation of interleukin 6 and transforming growth factor \u03b21 with peripheral blood regulatory T cells in rheumatoid arthritis patients: A potential biomarker","volume":"43","author":"Khoshmirsafa","year":"2018","journal-title":"Cent. J. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Li, Y., Jia, Y., Cui, T., and Zhang, J. (2021). IL-6\/STAT3 signaling pathway regulates the proliferation and damage of intestinal epithelial cells in patients with ulcerative colitis via H3K27ac. Exp. Ther. Med., 22.","DOI":"10.3892\/etm.2021.10322"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1007\/s00384-018-3069-8","article-title":"Evaluation of interleukin-6 and its soluble receptor components sIL-6R and sgp130 as markers of inflammation in inflammatory bowel diseases","volume":"33","author":"Nikolaus","year":"2018","journal-title":"Int. J. Colorectal Dis."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Sorokina, M., Merseburger, P., Rajan, K., Yirik, M.A., and Steinbeck, C. (2021). COCONUT online: Collection of Open Natural Products database. J. Cheminform., 13.","DOI":"10.1186\/s13321-020-00478-9"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.ddtec.2004.11.007","article-title":"Lead- and drug-like compounds: The rule-of-five revolution","volume":"1","author":"Lipinski","year":"2004","journal-title":"Drug Discov. Today Technol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Tran, Q.H., Nguyen, Q.T., Vo, N.Q.H., Mai, T.T., Tran, T.T.N., Tran, T.D., Le, M.T., Trinh, D.T.T., and Minh Thai, K. (2022). Structure-based 3D-Pharmacophore modeling to discover novel interleukin 6 inhibitors: An in silico screening, molecular dynamics simulations and binding free energy calculations. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0266632"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"23629","DOI":"10.1039\/C8RA01854E","article-title":"Design and virtual screening of novel fluoroquinolone analogs as effective mutant DNA GyrA inhibitors against urinary tract infection-causing fluoroquinolone resistant Escherichia coli","volume":"8","author":"Balasubramaniyan","year":"2018","journal-title":"RSC Adv."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.csbj.2019.02.006","article-title":"Ligand-based Pharmacophore Modeling, Virtual Screening and Molecular Docking Studies for Discovery of Potential Topoisomerase I Inhibitors","volume":"17","author":"Pal","year":"2019","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1021\/ci00024a018","article-title":"Analysis of Conformational Coverage. 1. Validation and Estimation of Coverage","volume":"35","author":"Smellie","year":"1995","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1002\/1097-0134(20010501)43:2<113::AID-PROT1023>3.0.CO;2-T","article-title":"High throughput docking for library design and library prioritization","volume":"43","author":"Diller","year":"2001","journal-title":"Proteins Struct. Funct. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.1021\/ci800081s","article-title":"Fully automated molecular mechanics based induced fit protein-ligand docking method","volume":"48","author":"Koska","year":"2008","journal-title":"J. Chem. Inf. Model."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1006\/jmbi.1996.0897","article-title":"Development and validation of a genetic algorithm for flexible docking","volume":"267","author":"Jones","year":"1997","journal-title":"J. Mol. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1021\/jm050540c","article-title":"Novel procedure for modeling ligand\/receptor induced fit effects","volume":"49","author":"Sherman","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1172\/JCI116300","article-title":"Pathological and immunological effects of ingesting L-tryptophan and 1,1\u2032-ethylidenebis (L-tryptophan) in Lewis rats","volume":"91","author":"Love","year":"1993","journal-title":"J. Clin. Investig."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1007\/BF01541175","article-title":"1,1\u2032-Ethylidenebis(tryptophan) (peak E) induces functional activation of human eosinophils and interleukin 5 production from T lymphocytes: Association of eosinophilia-myalgia syndrome with a l-tryptophan contaminant","volume":"14","author":"Yamaoka","year":"1994","journal-title":"J. Clin. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1023\/A:1018941328702","article-title":"Role of P-glycoprotein on the CNS disposition of amprenavir (141W94), an HIV protease inhibitor","volume":"16","author":"Polli","year":"1999","journal-title":"Pharm. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1080\/1062936X.2021.1939149","article-title":"Insights into effect of the Asp25\/Asp25\u2032 protonation states on binding of inhibitors Amprenavir and MKP97 to HIV-1 protease using molecular dynamics simulations and MM-GBSA calculations","volume":"32","author":"Yu","year":"2021","journal-title":"SAR QSAR Environ. Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"823","DOI":"10.3892\/ijo.2017.3860","article-title":"Repositioning of amprenavir as a novel extracellular signal-regulated kinase-2 inhibitor and apoptosis inducer in MCF-7 human breast cancer","volume":"50","author":"Jiang","year":"2017","journal-title":"Int. J. Oncol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1038\/s41596-020-0312-x","article-title":"The HDOCK server for integrated protein\u2013protein docking","volume":"15","author":"Yan","year":"2020","journal-title":"Nat. Protoc."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2101","DOI":"10.1126\/science.1083901","article-title":"Hexameric structure and assembly of the interieukin-6\/IL-6 \u03b1-receptor\/gp130 complex","volume":"300","author":"Boulanger","year":"2003","journal-title":"Science"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"D833","DOI":"10.1093\/nar\/gkw943","article-title":"DisGeNET: A comprehensive platform integrating information on human disease-associated genes and variants","volume":"45","author":"Bravo","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Szklarczyk, D., Gable, A.L., Lyon, D., Junge, A., Wyder, S., Huerta-Cepas, J., Simonovic, M., Doncheva, N.T., Morris, J.H., and Bork, P. (2019). STRING v11: Protein\u2013protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res., 47.","DOI":"10.1093\/nar\/gky1131"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Kuleshov, M.V., Jones, M.R., Rouillard, A.D., Fernandez, N.F., Duan, Q., Wang, Z., Koplev, S., Jenkins, S.L., Jagodnik, K.M., and Lachmann, A. (2016). Enrichr: A comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res., 44.","DOI":"10.1093\/nar\/gkw377"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Chen, E.Y., Tan, C.M., Kou, Y., Duan, Q., Wang, Z., Meirelles, G.V., Clark, N.R., and Ma\u2019ayan, A. (2013). Enrichr: Interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinform., 14.","DOI":"10.1186\/1471-2105-14-128"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1093\/emboj\/16.5.989","article-title":"1.9 A crystal structure of interleukin 6: Implications for a novel mode of receptor dimerization and signaling","volume":"16","author":"Somers","year":"1997","journal-title":"EMBO J."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1963","DOI":"10.1007\/s11030-021-10211-9","article-title":"Identification of potential plant-based inhibitor against viral proteases of SARS-CoV-2 through molecular docking, MM-PBSA binding energy calculations and molecular dynamics simulation","volume":"25","author":"Gogoi","year":"2021","journal-title":"Mol. Divers."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1002\/jcc.21367","article-title":"CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields","volume":"31","author":"Vanommeslaeghe","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.1021\/acs.jcim.5b00559","article-title":"ZINC 15\u2014Ligand Discovery for Everyone","volume":"55","author":"Sterling","year":"2015","journal-title":"J. Chem. Inf. Model."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Yang, W., Wang, S., Zhang, X., Sun, H., Zhang, M., Chen, H., Cui, J., Li, J., Peng, F., and Zhu, M. (2023). New natural compound inhibitors of PDGFRA (platelet-derived growth factor receptor \u03b1) based on computational study for high\u2013grade glioma therapy. Front. Neurosci., 16.","DOI":"10.3389\/fnins.2022.1060012"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/19\/10600\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:08:49Z","timestamp":1760112529000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/19\/10600"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,1]]},"references-count":68,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["ijms251910600"],"URL":"https:\/\/doi.org\/10.3390\/ijms251910600","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2024,10,1]]}}}