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Given the historical use of Traditional Chinese Medicine (TCM) in the management of respiratory diseases, phenylethanoid glycosides (PGs) represent an attractive and chemically diverse natural product scaffold for the discovery of antiviral agents. Objectives: This study aimed to identify promising candidates within this class capable of simultaneously inhibiting both target proteases. Methods: The PG structures described in the literature between 1950 and 2020 were gathered and curated to construct a dedicated database, which was subsequently subjected to virtual screening. In silico ADMETox predictions and 2D ligand\u2013protein interaction analyses were then employed to evaluate the identified hit PGs. Ligand stability within the binding sites of the proteases was further assessed using free energy landscape (FEL) and MM\/GBSA calculations, while enzymatic inhibition of the commercial PG was evaluated via FRET assays. Results: Virtual screening identified 22 PGs with multitarget potential, predominantly sourced from Asia, followed by the Americas and Europe. The hit compound magnoloside I is found in Magnolia officinalis, a species widely used in TCM for respiratory conditions and officially prescribed during the COVID-19 pandemic. A second hit, calceolarioside B, inhibited more than 90% of the enzymatic activity of both proteases in the FRET assay. Conclusions: Together, these findings highlight phenylethanoid glycosides as promising scaffolds for dual protease inhibition.<\/jats:p>","DOI":"10.3390\/ph19071126","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T15:17:52Z","timestamp":1784647072000},"page":"1126","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Computational Evaluation of Multitarget Capabilities of Phenylethanoid Glycosides Against SARS-CoV-2\u2019s 3CLpro and PLpro"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2029-235X","authenticated-orcid":false,"given":"Maria Eduarda","family":"Alves Esteves","sequence":"first","affiliation":[{"name":"Programa de Biologia Computacional e Sistemas, Instituto Oswaldo Cruz, Rio de Janeiro 21045-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9820-9982","authenticated-orcid":false,"given":"Bruce","family":"Veiga Andriolo","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Biotecnologia, Instituto Nacional de Metrologia, Qualidade e Tecnologia, Duque de Caxias, Rio de Janeiro 25250-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7826-9139","authenticated-orcid":false,"given":"Caio Felipe de Araujo Ribas","family":"Cheohen","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o Multic\u00eantrico em Ci\u00eancias Fisiol\u00f3gicas, Universidade Federal do Rio de Janeiro, Maca\u00e9 27965-045, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6523-6749","authenticated-orcid":false,"given":"Thamirys Silva","family":"da Fonseca","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Ci\u00eancias Farmac\u00eauticas, Faculdade de Farm\u00e1cia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3032-3148","authenticated-orcid":false,"given":"Mariana","family":"Freire Campos","sequence":"additional","affiliation":[{"name":"Departamento de Produtos Naturais e Alimentos, Faculdade de Farm\u00e1cia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2542-729X","authenticated-orcid":false,"given":"Carla Monteiro","family":"Leal","sequence":"additional","affiliation":[{"name":"Departamento de Produtos Naturais e Alimentos, Faculdade de Farm\u00e1cia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1410-480X","authenticated-orcid":false,"given":"Diego","family":"Allonso","sequence":"additional","affiliation":[{"name":"Departamento de Biotecnologia Farmac\u00eautica, Faculdade de Farm\u00e1cia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2577-3993","authenticated-orcid":false,"given":"Gilda Guimar\u00e3es","family":"Leit\u00e3o","sequence":"additional","affiliation":[{"name":"Instituto de Pesquisas de Produtos Naturais, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7445-074X","authenticated-orcid":false,"given":"Suzana Guimar\u00e3es","family":"Leit\u00e3o","sequence":"additional","affiliation":[{"name":"Departamento de Produtos Naturais e Alimentos, Faculdade de Farm\u00e1cia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil"},{"name":"Laborat\u00f3rio de Fitoqu\u00edmica e Farmacognosia, Centro de Ci\u00eancias da Sa\u00fade, Faculdade de Farm\u00e1cia, Universidade Federal do Rio de Janeiro, Bloco A, Sala 10, 2\u00ba Andar, Av. 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Lett."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/s42003-020-01577-x","article-title":"Identification of 3-Chymotrypsin like Protease (3CLPro) Inhibitors as Potential Anti-SARS-CoV-2 Agents","volume":"4","author":"Mody","year":"2021","journal-title":"Commun. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1007\/BF02174046","article-title":"Viral Cysteine Proteinases","volume":"6","author":"Gorbalenya","year":"1996","journal-title":"Perspect. Drug Discov. Des."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1038\/s41467-021-21060-3","article-title":"Structure of Papain-like Protease from SARS-CoV-2 and Its Complexes with Non-Covalent Inhibitors","volume":"12","author":"Osipiuk","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.apsb.2020.08.014","article-title":"Crystal Structure of SARS-CoV-2 Papain-like Protease","volume":"11","author":"Gao","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Bosken, Y.K., Cholko, T., Lou, Y.-C., Wu, K.-P., and Chang, C.A. (2020). Insights into Dynamics of Inhibitor and Ubiquitin-Like Protein Binding in SARS-CoV-2 Papain-Like Protease. Front. Mol. Biosci., 7.","DOI":"10.3389\/fmolb.2020.00174"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Singla, R.K., He, X., Chopra, H., Tsagkaris, C., Shen, L., Kamal, M.A., and Shen, B. (2021). Natural Products for the Prevention and Control of the COVID-19 Pandemic: Sustainable Bioresources. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.758159"},{"key":"ref_10","first-page":"1158","article-title":"Effectiveness of Paxlovid in Reducing Severe Coronavirus Disease 2019 and Mortality in High-Risk Patients","volume":"76","author":"Gronich","year":"2022","journal-title":"Clin. Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"26065","DOI":"10.1039\/D5RA03213J","article-title":"In Vitro and in Silico Studies of the SARS-CoV-2 Main Protease Inhibition and Antioxidant Activities of Isolated Compounds from Marrubium alysson L","volume":"15","author":"Ezz","year":"2025","journal-title":"RSC Adv."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"130377","DOI":"10.1016\/j.ijbiomac.2024.130377","article-title":"Discovery of Natural Catechol Derivatives as Covalent SARS-CoV-2 3CLpro Inhibitors","volume":"264","author":"Wang","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1007\/s11684-021-0853-6","article-title":"Effects of Shuanghuanglian Oral Liquids on Patients with COVID-19: A Randomized, Open-Label, Parallel-Controlled, Multicenter Clinical Trial","volume":"15","author":"Ni","year":"2021","journal-title":"Front. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"110641","DOI":"10.1016\/j.biopha.2020.110641","article-title":"Lianhua Qingwen Prescription for Coronavirus Disease 2019 (COVID-19) Treatment: Advances and Prospects","volume":"130","author":"Li","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1038\/s41401-020-0483-6","article-title":"Anti-SARS-CoV-2 Activities in Vitro of Shuanghuanglian Preparations and Bioactive Ingredients","volume":"41","author":"Su","year":"2020","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Lu, Y.-C., Tseng, L.-W., Huang, Y.-C., Yang, C.-W., Chen, Y.-C., and Chen, H.-Y. (2022). The Potential Complementary Role of Using Chinese Herbal Medicine with Western Medicine in Treating COVID-19 Patients: Pharmacology Network Analysis. Pharmaceuticals, 15.","DOI":"10.3390\/ph15070794"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/s41392-022-01249-8","article-title":"Small Molecules in the Treatment of COVID-19","volume":"7","author":"Lei","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Zeng, M., Li, L., and Wu, Z. (2020). Traditional Chinese Medicine Lianhua Qingwen Treating Corona Virus Disease 2019(COVID-19): Meta-Analysis of Randomized Controlled Trials. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0238828"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s13020-020-00326-w","article-title":"The Potential Insights of Traditional Chinese Medicine on Treatment of COVID-19","volume":"15","author":"Tong","year":"2020","journal-title":"Chin. Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Gao, B., Zhu, H., Liu, Z., He, X., Sun, J., Li, Y., Wu, X., Pehrsson, P., Zhang, Y., and Yao, Y. (2024). Chemical Compositions of Lianqiao (Forsythia suspensa) Extracts and Their Potential Health Benefits. Pharmaceuticals, 17.","DOI":"10.3390\/ph17060740"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1016\/j.csbj.2023.02.020","article-title":"In Silico Screening of Phenylethanoid Glycosides, a Class of Pharmacologically Active Compounds as Natural Inhibitors of SARS-CoV-2 Proteases","volume":"21","author":"Esteves","year":"2023","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"131394","DOI":"10.1016\/j.molstruc.2021.131394","article-title":"Molecular Docking and Dynamics Studies of Nicotinamide Riboside as a Potential Multi-Target Nutraceutical against SARS-CoV-2 Entry, Replication, and Transcription: A New Insight","volume":"1247","author":"Esam","year":"2022","journal-title":"J. Mol. Struct."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"417","DOI":"10.2217\/fmb-2022-0025","article-title":"Evasion of Vaccine-Induced Humoral Immunity by Emerging Sub-Variants of SARS-CoV-2","volume":"17","author":"Koyama","year":"2022","journal-title":"Future Microbiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1016\/j.jinf.2022.03.014","article-title":"Influence of Vaccination and Prior Immunity on the Dynamics of Omicron BA.1 and BA.2 Sub-Variants","volume":"84","author":"Dimeglio","year":"2022","journal-title":"J. Infect."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1056\/NEJMoa2118542","article-title":"Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19","volume":"386","author":"Hammond","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"102329","DOI":"10.1016\/j.dsx.2021.102329","article-title":"Molnupiravir in COVID-19: A Systematic Review of Literature","volume":"15","author":"Singh","year":"2021","journal-title":"Diabetes Metab. Syndr. Clin. Res. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2592","DOI":"10.2174\/092986708785908996","article-title":"Naturally Occurring Phenylethanoid Glycosides: Potential Leads for New Therapeutics","volume":"15","author":"Fu","year":"2008","journal-title":"Curr. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.jmii.2020.03.022","article-title":"Genotype and Phenotype of COVID-19: Their Roles in Pathogenesis","volume":"54","author":"Mousavizadeh","year":"2021","journal-title":"J. Microbiol. Immunol. Infect."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"153242","DOI":"10.1016\/j.phymed.2020.153242","article-title":"Efficacy and Safety of Lianhuaqingwen Capsules, a Repurposed Chinese Herb, in Patients with Coronavirus Disease 2019: A Multicenter, Prospective, Randomized Controlled Trial","volume":"85","author":"Hu","year":"2021","journal-title":"Phytomedicine"},{"key":"ref_30","unstructured":"Royal Botanic Gardens, Kew (2023, July 04). Plants of the World Online. Available online: https:\/\/powo.science.kew.org\/."},{"key":"ref_31","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_32","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1073\/pnas.70.8.2281","article-title":"Carcinogens Are Mutagens: A Simple Test Combining Liver Homogenates for Activation and Bacteria for Detection","volume":"70","author":"Ames","year":"1973","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1021\/acs.molpharmaceut.0c00608","article-title":"COVID-19 Transmission, Current Treatment, and Future Therapeutic Strategies","volume":"18","author":"Salian","year":"2021","journal-title":"Mol. Pharm."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Guo, M.-X., Zhang, M.-M., Yang, H.-Y., Zhang, C.-L., Cheng, H.-Y., Li, N.-Z., Yi, L.-T., and Zhu, J.-X. (2022). Lagotis Brachystachya Maxim Attenuates Chronic Alcoholic Liver Injury Combined with Gouty Arthritis in Rats via Its Anti-Inflammatory Activity. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.995777"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"117055","DOI":"10.1016\/j.jep.2023.117055","article-title":"Evaluation of the Anti-Inflammatory Material Basis of Lagotis Brachystachya in HepG2 and THP-1 Cells","volume":"318","author":"Zhu","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"114524","DOI":"10.1016\/j.jep.2021.114524","article-title":"The Rich Pharmacological Activities of Magnolia Officinalis and Secondary Effects Based on Significant Intestinal Contributions","volume":"281","author":"Niu","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"153297","DOI":"10.1016\/j.phymed.2020.153297","article-title":"Therapeutic Options of TCM for Organ Injuries Associated with COVID-19 and the Underlying Mechanism","volume":"85","author":"Zhang","year":"2021","journal-title":"Phytomedicine"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Silveira, D., Prieto-Garcia, J.M., Boylan, F., Estrada, O., Fonseca-Bazzo, Y.M., Jamal, C.M., Magalh\u00e3es, P.O., Pereira, E.O., Tomczyk, M., and Heinrich, M. (2020). COVID-19: Is There Evidence for the Use of Herbal Medicines as Adjuvant Symptomatic Therapy?. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.581840"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1021\/np9002383","article-title":"Phenylethanoid Glycosides from Lantana Fucata with in Vitro Anti-Inflammatory Activity","volume":"72","author":"Piccinelli","year":"2009","journal-title":"J. Nat. Prod."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"115038","DOI":"10.1016\/j.jep.2022.115038","article-title":"Chemical Profiling and Unraveling of Anti-COVID-19 Biomarkers of Red Sage (Lantana camara L.) Cultivars Using UPLC-MS\/MS Coupled to Chemometric Analysis, in Vitro Study and Molecular Docking","volume":"291","author":"Darwish","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1080\/14786419.2022.2103125","article-title":"Isolation and Structural Characterization of Phytoconstituents from Leaves of Bignonia Binata","volume":"38","author":"Samy","year":"2024","journal-title":"Nat. Prod. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/j.jep.2006.08.003","article-title":"Brazilian Plants with Possible Action on the Central Nervous System\u2014A Study of Historical Sources from the 16th to 19th Century","volume":"109","author":"Giorgetti","year":"2007","journal-title":"J. Ethnopharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"116614","DOI":"10.1016\/j.bmc.2022.116614","article-title":"Structural Modification Aimed for Improving Solubility of Lead Compounds in Early Phase Drug Discovery","volume":"56","author":"Das","year":"2022","journal-title":"Bioorg. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1039\/D0RA09621K","article-title":"Amino Acid Ester-Coupled Caffeoylquinic Acid Derivatives as Potential Hypolipidemic Agents: Synthesis and Biological Evaluation","volume":"11","author":"Zhang","year":"2021","journal-title":"RSC Adv."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.ijpharm.2008.06.018","article-title":"Pharmacokinetics of Amino Acid Ester Prodrugs of Acyclovir after Oral Administration: Interaction with the Transporters on Caco-2 Cells","volume":"362","author":"Katragadda","year":"2008","journal-title":"Int. J. Pharm."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.enzmictec.2016.02.003","article-title":"Methylation of Flavonoids: Chemical Structures, Bioactivities, Progress and Perspectives for Biotechnological Production","volume":"86","author":"Koirala","year":"2016","journal-title":"Enzym. Microb. Technol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"12500","DOI":"10.1021\/acs.jmedchem.2c01005","article-title":"Targeting SARS-CoV-2 Main Protease for Treatment of COVID-19: Covalent Inhibitors Structure\u2013Activity Relationship Insights and Evolution Perspectives","volume":"65","author":"Bono","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"20808","DOI":"10.1038\/s41598-020-77794-5","article-title":"Conserved Interactions Required for Inhibition of the Main Protease of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)","volume":"10","author":"Shitrit","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1126\/science.abl4784","article-title":"An Oral SARS-CoV-2 Mpro Inhibitor Clinical Candidate for the Treatment of COVID-19","volume":"374","author":"Owen","year":"2021","journal-title":"Science"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1038\/s41467-020-20718-8","article-title":"The Complex Structure of GRL0617 and SARS-CoV-2 PLpro Reveals a Hot Spot for Antiviral Drug Discovery","volume":"12","author":"Fu","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1039\/NP9941100591","article-title":"Phenylethanoid Glycosides in Plants: Structure and Biological Activity","volume":"11","author":"Riguera","year":"1994","journal-title":"Nat. Prod. Rep."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Xue, Z., and Yang, B. (2016). Phenylethanoid Glycosides: Research Advances in Their Phytochemistry, Pharmacological Activity and Pharmacokinetics. Molecules, 21.","DOI":"10.3390\/molecules21080991"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2605","DOI":"10.1002\/med.21717","article-title":"Therapeutic Potential of Phenylethanoid Glycosides: A Systematic Review","volume":"40","author":"Wu","year":"2020","journal-title":"Med. Res. Rev."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"W522","DOI":"10.1093\/nar\/gkm276","article-title":"PDB2PQR: Expanding and Upgrading Automated Preparation of Biomolecular Structures for Molecular Simulations","volume":"35","author":"Dolinsky","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1758-2946-3-33","article-title":"Open Babel: An Open Chemical Toolbox","volume":"3","author":"Banck","year":"2011","journal-title":"J. Cheminform."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1038\/nprot.2016.051","article-title":"Computational Protein\u2013Ligand Docking and Virtual Drug Screening with the AutoDock Suite","volume":"11","author":"Forli","year":"2016","journal-title":"Nat. Protoc."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1007\/s10822-012-9551-4","article-title":"Pose Prediction and Virtual Screening Performance of GOLD Scoring Functions in a Standardized Test","volume":"26","author":"Liebeschuetz","year":"2012","journal-title":"J. Comput. Aided. Mol. Des."},{"key":"ref_58","unstructured":"Schr\u00f6dinger (Schr\u00f6dinger Release 2022-3: Maestro, 2021). Schr\u00f6dinger Release 2022-3: Maestro, version 13.1.141."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"W5","DOI":"10.1093\/nar\/gkab255","article-title":"ADMETlab 2.0: An Integrated Online Platform for Accurate and Comprehensive Predictions of ADMET Properties","volume":"49","author":"Xiong","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_60","unstructured":"Case, D., Aktulga, H.M., Belfon, K., Ben-Shalom, I., Brozell, S., Cerutti, D., Cheatham, T., Cisneros, G.A., Cruzeiro, V., and Darden, T. (2022). Amber 2022, University of California, San Francisco."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"W368","DOI":"10.1093\/nar\/gki464","article-title":"H++: A Server for Estimating PKas and Adding Missing Hydrogens to Macromolecules","volume":"33","author":"Gordon","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"W537","DOI":"10.1093\/nar\/gks375","article-title":"H++ 3.0: Automating PK Prediction and the Preparation of Biomolecular Structures for Atomistic Molecular Modeling and Simulations","volume":"40","author":"Anandakrishnan","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1021\/acs.jcim.5b00674","article-title":"MCPB.Py: A Python Based Metal Center Parameter Builder","volume":"56","author":"Li","year":"2016","journal-title":"J. Chem. Inf. Model."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"5188","DOI":"10.1063\/5.0005188","article-title":"Recent Developments in the General Atomic and Molecular Electronic Structure System","volume":"152","author":"Barca","year":"2020","journal-title":"J. Chem. Phys."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1021\/acs.jctc.9b00591","article-title":"Ff19SB: Amino-Acid-Specific Protein Backbone Parameters Trained against Quantum Mechanics Energy Surfaces in Solution","volume":"16","author":"Tian","year":"2020","journal-title":"J. Chem. Theory Comput."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1002\/jcc.20035","article-title":"Development and Testing of a General Amber Force Field","volume":"25","author":"Wang","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3863","DOI":"10.1021\/jz501780a","article-title":"Building Water Models: A Different Approach","volume":"5","author":"Izadi","year":"2014","journal-title":"J. Phys. Chem. Lett."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1021\/acs.jctc.9b00953","article-title":"Split the Charge Difference in Two! A Rule of Thumb for Adding Proper Amounts of Ions in MD Simulations","volume":"16","author":"Machado","year":"2020","journal-title":"J. Chem. Theory Comput."},{"key":"ref_69","unstructured":"(2023, July 04). PepIntProt (PIP): Peptide-Protein Interaction Profiler from Molecular Dynamics Simulations, Available online: https:\/\/github.com\/vbonatto11\/PepIntProt."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/7\/1126\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T09:28:25Z","timestamp":1784712505000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/7\/1126"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,21]]},"references-count":69,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ph19071126"],"URL":"https:\/\/doi.org\/10.3390\/ph19071126","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,21]]}}}