{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T07:18:22Z","timestamp":1791962302563,"version":"4.3.4"},"reference-count":64,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T00:00:00Z","timestamp":1764806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fundamental Fund of Khon Kaen University"},{"DOI":"10.13039\/501100004704","name":"National Research Council of Thailand","doi-asserted-by":"crossref","award":["N34A670082"],"award-info":[{"award-number":["N34A670082"]}],"id":[{"id":"10.13039\/501100004704","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology (MEXT) in Japan","doi-asserted-by":"crossref","award":["23H04879"],"award-info":[{"award-number":["23H04879"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Japan Agency for Science and Technology","award":["JPMJCR20B3"],"award-info":[{"award-number":["JPMJCR20B3"]}]},{"name":"center for Quantum Information LifeScience (QiLS) at the University of Tsukuba"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Dengue virus (DENV) and Zika virus (ZIKV) are flaviviruses transmitted by Aedes spp. mosquitoes, causing a spectrum of symptoms ranging from mild fevers and joint pain to severe damage to vital organs, including the kidneys, brain, and liver. Unfortunately, there are currently no specific treatments for these viruses. The NS2B\/NS3 serine protease has been recognized as a crucial therapeutic target due to its pivotal role in viral replication. Herein, several molecular modeling techniques were employed to search for novel allosteric inhibitors against DENV and ZIKV NS2B\/NS3 proteases from a set of 545 in-house compounds. Virtual screening based on molecular docking and MM\/GBSA-based free energy calculations indicated that, among 545 derivatives, four compounds demonstrated high binding affinity against both targets, including two sulfonamide-vinyl sulfone hybrids (cpd48_e and cpd50_e), one sulfonamide-chalcone analog (cpd48), and one berberine-cinnamic acid derivative (DN071_f). Their molecular complexation was driven mainly by van der Waals forces rather than electrostatic attraction. Several residues at the enzyme allosteric site, particularly K74, L149, and N152 (DENV) and L76, I123, N152, and V155 (ZIKV), were identified as binding hotspots for the screened compounds. Drug-likeness predictions based on Lipinski\u2019s rule of five further supported their potential as drug candidates. Overall, these findings provide valuable insights for the future design and development of novel antiviral drugs targeting the DENV and ZIKV NS2B\/NS3 proteases.<\/jats:p>","DOI":"10.3390\/ijms262311762","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T10:50:38Z","timestamp":1764931838000},"page":"11762","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Identification of Sulfonamide-Vinyl Sulfone\/Chalcone and Berberine-Cinnamic Acid Hybrids as Potent DENV and ZIKV NS2B\/NS3 Allosteric Inhibitors"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4389-334X","authenticated-orcid":false,"given":"Panupong","family":"Mahalapbutr","sequence":"first","affiliation":[{"name":"Department of Biochemistry, and Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kowit","family":"Hengphasatporn","sequence":"additional","affiliation":[{"name":"Center for Computational Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wachirapol","family":"Manimont","sequence":"additional","affiliation":[{"name":"Center of Excellence in Computational Chemistry (CECC), Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ladawan","family":"Vajarintarangoon","sequence":"additional","affiliation":[{"name":"Center of Excellence in Structural and Computational Biology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3219-6007","authenticated-orcid":false,"given":"Yasuteru","family":"Shigeta","sequence":"additional","affiliation":[{"name":"Center for Computational Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nayana","family":"Bhat","sequence":"additional","affiliation":[{"name":"Center of Excellence in Structural and Computational Biology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8155-1602","authenticated-orcid":false,"given":"Thitinan","family":"Aiebchun","sequence":"additional","affiliation":[{"name":"Center of Excellence in Structural and Computational Biology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bodee","family":"Nutho","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Supot","family":"Hannongbua","sequence":"additional","affiliation":[{"name":"Center of Excellence in Computational Chemistry (CECC), Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7402-3235","authenticated-orcid":false,"given":"Thanyada","family":"Rungrotmongkol","sequence":"additional","affiliation":[{"name":"Center of Excellence in Structural and Computational Biology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Silva, N.M., Santos, N.C., and Martins, I.C. (2020). Dengue and Zika Viruses: Epidemiological History, Potential Therapies, and Promising Vaccines. Trop. Med. Infect. Dis., 5.","DOI":"10.3390\/tropicalmed5040150"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1186\/s13071-023-05778-1","article-title":"Co-infection of dengue and Zika viruses mutually enhances viral replication in the mosquito Aedes aegypti","volume":"16","author":"Lin","year":"2023","journal-title":"Parasites Vectors"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"100555","DOI":"10.1016\/j.onehlt.2023.100555","article-title":"Aedes aegypti and Aedes albopictus (Diptera: Culicidae) ecology, biology, behaviour, and implications on arbovirus transmission in Thailand: Review","volume":"16","author":"Ahebwa","year":"2023","journal-title":"One Health"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Sekaran, S.D., Ismail, A.A., Thergarajan, G., Chandramathi, S., Rahman, S.K.H., Mani, R.R., Jusof, F.F., Lim, Y.A.L., and Manikam, R. (2022). Host immune response against DENV and ZIKV infections. Front. Cell. Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.975222"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3","DOI":"10.4103\/0974-777X.176140","article-title":"The Emergence of Zika Virus as a Global Health Security Threat: A Review and a Consensus Statement of the INDUSEM Joint working Group (JWG)","volume":"8","author":"Stawicki","year":"2016","journal-title":"J. Glob. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Chuang, F.-K., Liao, C.-L., Hu, M.-K., Chiu, Y.-L., Lee, A.-R., Huang, S.-M., Chiu, Y.-L., Tsai, P.-L., Su, B.-C., and Chang, T.-H. (2020). Antiviral Activity of Compound L3 against Dengue and Zika Viruses In Vitro and In Vivo. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21114050"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1186\/s13567-021-00966-2","article-title":"Structure and function of capsid protein in flavivirus infection and its applications in the development of vaccines and therapeutics","volume":"52","author":"Zhang","year":"2021","journal-title":"Vet. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"745","DOI":"10.2217\/fvl-2016-0106","article-title":"Why should we target viral serine proteases when developing antiviral agents?","volume":"11","author":"Grzywa","year":"2016","journal-title":"Future Virol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.jmgm.2019.08.001","article-title":"Binding recognition of substrates in NS2B\/NS3 serine protease of Zika virus revealed by molecular dynamics simulations","volume":"92","author":"Nutho","year":"2019","journal-title":"J. Mol. Graph. Model."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2744","DOI":"10.1021\/cb400612h","article-title":"Allosteric Inhibition of the NS2B-NS3 Protease from Dengue Virus","volume":"8","author":"Yildiz","year":"2013","journal-title":"ACS Chem. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Zephyr, J., Rao, D.N., Johnson, C., Shaqra, A.M., Nalivaika, E.A., Jordan, A., Yilmaz, N.K., Ali, A., and Schiffer, C.A. (2023). Allosteric quinoxaline-based inhibitors of the flavivirus NS2B\/NS3 protease. Bioorg. Chem., 131.","DOI":"10.1016\/j.bioorg.2022.106269"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Brecher, M., Li, Z., Liu, B., Zhang, J., Koetzner, C.A., Alifarag, A., Jones, S.A., Lin, Q., Kramer, L.D., and Li, H. (2017). A conformational switch high-throughput screening assay and allosteric inhibition of the flavivirus NS2B-NS3 protease. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006411"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"11359","DOI":"10.1021\/acs.jmedchem.9b01697","article-title":"Proline-Based Allosteric Inhibitors of Zika and Dengue Virus NS2B\/NS3 Proteases","volume":"62","author":"Millies","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Meewan, I., Shiryaev, S.A., Kattoula, J., Huang, C.-T., Lin, V., Chuang, C.-H., Terskikh, A.V., and Abagyan, R. (2023). Allosteric Inhibitors of Zika Virus NS2B-NS3 Protease Targeting Protease in \u201cSuper-Open\u201d Conformation. Viruses, 15.","DOI":"10.3390\/v15051106"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Gangopadhyay, A., and Saha, A. (2023). Exploring allosteric hits of the NS2B-NS3 protease of DENV2 by structure-guided screening. Comput. Biol. Chem., 104.","DOI":"10.1016\/j.compbiolchem.2023.107876"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1080\/14756366.2018.1507029","article-title":"Computational screening of chalcones acting against topoisomerase II\u03b1 and their cytotoxicity towards cancer cell lines","volume":"34","author":"Sangpheak","year":"2019","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Sangpheak, K., Tabtimmai, L., Seetaha, S., Rungnim, C., Chavasiri, W., Wolschann, P., Choowongkomon, K., and Rungrotmongkol, T. (2019). Biological Evaluation and Molecular Dynamics Simulation of Chalcone Derivatives as Epidermal Growth Factor-Tyrosine Kinase Inhibitors. Molecules, 24.","DOI":"10.3390\/molecules24061092"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Aiebchun, T., Mahalapbutr, P., Auepattanapong, A., Khaikate, O., Seetaha, S., Tabtimmai, L., Kuhakarn, C., Choowongkomon, K., and Rungrotmongkol, T. (2021). Identification of Vinyl Sulfone Derivatives as EGFR Tyrosine Kinase Inhibitor: In Vitro and In Silico Studies. Molecules, 26.","DOI":"10.3390\/molecules26082211"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"19645","DOI":"10.1021\/acsomega.3c01195","article-title":"Sulfonylated Indeno[1,2-c]quinoline Derivatives as Potent EGFR Tyrosine Kinase Inhibitors","volume":"8","author":"Hengphasatporn","year":"2023","journal-title":"ACS Omega"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Nguyen, D.V., Hengphasatporn, K., Danova, A., Suroengrit, A., Boonyasuppayakorn, S., Fujiki, R., Shigeta, Y., Rungrotmongkol, T., and Chavasiri, W. (2023). Structure-yeast \u03b1-glucosidase inhibitory activity relationship of 9-O-berberrubine carboxylates. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-45116-0"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Mottin, M., Caesar, L.K., Brodsky, D., Mesquita, N.C., de Oliveira, K.Z., Noske, G.D., Sousa, B.K., Ramos, P.R., Jarmer, H., and Loh, B. (2022). Chalcones from Angelica keiskei (ashitaba) inhibit key Zika virus replication proteins. Bioorg. Chem., 120.","DOI":"10.1016\/j.bioorg.2022.105649"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"115227","DOI":"10.1016\/j.ejmech.2023.115227","article-title":"N-sulfonyl peptide-hybrids as a new class of dengue virus protease inhibitors","volume":"251","author":"Behrouz","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5567111","DOI":"10.1155\/2021\/5567111","article-title":"Designs, Synthesis, Docking Studies, and Biological Evaluation of Novel Berberine Derivatives Targeting Zika Virus","volume":"2021","author":"Nguyen","year":"2021","journal-title":"J. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2798","DOI":"10.1021\/acsomega.1c05569","article-title":"Myricetin Allosterically Inhibits the Dengue NS2B-NS3 Protease by Disrupting the Active and Locking the Inactive Conformations","volume":"7","author":"Dang","year":"2022","journal-title":"ACS Omega"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s13065-018-0435-0","article-title":"4-Thiazolidinone coumarin derivatives as two-component NS2B\/NS3 DENV flavivirus serine protease inhibitors: Synthesis, molecular docking, biological evaluation and structure-activity relationship studies","volume":"12","author":"Yusufzai","year":"2018","journal-title":"Chem. Cent. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"108036","DOI":"10.1016\/j.dib.2022.108036","article-title":"The data on molecular docking of cinnamic acid amide on dengue viral target NS2B\/NS3","volume":"42","author":"Yusoff","year":"2022","journal-title":"Data Brief"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6832","DOI":"10.1021\/jacs.9b02505","article-title":"Discovery, X-ray Crystallography and Antiviral Activity of Allosteric Inhibitors of Flavivirus NS2B-NS3 Protease","volume":"141","author":"Yao","year":"2019","journal-title":"J. Am. Chem. Soc."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"85938","DOI":"10.1039\/C5RA14469H","article-title":"Reaching beyond HIV\/HCV: Nelfinavir as a potential starting point for broad-spectrum protease inhibitors against dengue and chikungunya virus","volume":"5","author":"Bhakat","year":"2015","journal-title":"RSC Adv."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"106220","DOI":"10.1016\/j.ejps.2022.106220","article-title":"The discovery of Zika virus NS2B-NS3 inhibitors with antiviral activity via an integrated virtual screening approach","volume":"175","author":"Mirza","year":"2022","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1021\/jm401788m","article-title":"Discovery of Vinyl Sulfones as a Novel Class of Neuroprotective Agents toward Parkinson\u2019s Disease Therapy","volume":"57","author":"Woo","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.bioorg.2015.07.005","article-title":"Synthesis and molecular modelling studies of novel sulphonamide derivatives as dengue virus 2 protease inhibitors","volume":"62","author":"Timiri","year":"2015","journal-title":"Bioorg. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Santos, L.H., Rocha, R.E.O., Dias, D.L., Ribeiro, B.M.R.M., Serafim, M.S.M., Abrah\u00e3o, J.S., and Ferreira, R.S. (2023). Evaluating Known Zika Virus NS2B-NS3 Protease Inhibitor Scaffolds via In Silico Screening and Biochemical Assays. Pharmaceuticals, 16.","DOI":"10.3390\/ph16091319"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3337","DOI":"10.1016\/j.bmcl.2005.12.075","article-title":"Inhibitory activity of cyclohexenyl chalcone derivatives and flavonoids of fingerroot, Boesenbergia rotunda (L.), towards dengue-2 virus NS3 protease","volume":"16","author":"Kiat","year":"2006","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"104","DOI":"10.5808\/GI.2016.14.3.104","article-title":"Virtual Screening for Potential Inhibitors of NS3 Protein of Zika Virus","volume":"14","author":"Sahoo","year":"2016","journal-title":"Genom. Inf."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.jmgm.2014.06.008","article-title":"Allosteric pocket of the dengue virus (serotype 2) NS2B\/NS3 protease: In silico ligand screening and molecular dynamics studies of inhibition","volume":"52","author":"Mukhametov","year":"2014","journal-title":"J. Mol. Graph. Model."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Costa, R.A.D., Rocha, J.A.D., Pinheiro, A.S., Costa, A.D.S.D., Rocha, E.C.D., Silva, R.C., Gon\u00e7alves, A.D.S., Santos, C.B., and Brasil, D.D.S. (2022). A Computational Approach Applied to the Study of Potential Allosteric Inhibitors Protease NS2B\/NS3 from Dengue Virus. Molecules, 27.","DOI":"10.3390\/molecules27134118"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Dharmapalan, B.T., Biswas, R., Sankaran, S., Venkidasamy, B., Thiruvengadam, M., George, G., Rebezov, M., Zengin, G., Gallo, M., and Montesano, D. (2022). Inhibitory Potential of Chromene Derivatives on Structural and Non-Structural Proteins of Dengue Virus. Viruses, 14.","DOI":"10.3390\/v14122656"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Rehman, H.M., Sajjad, M., Ali, M.A., Gul, R., Irfan, M., Naveed, M., Bhinder, M.A., Ghani, M.U., Hussain, N., and Said, A.S.A. (2023). Identification of NS2B-NS3 Protease Inhibitors for Therapeutic Application in ZIKV Infection: A Pharmacophore-Based High-Throughput Virtual Screening and MD Simulations Approaches. Vaccines, 11.","DOI":"10.3390\/vaccines11010131"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"18132","DOI":"10.1021\/acsomega.8b01002","article-title":"Hydroxychloroquine Inhibits Zika Virus NS2B-NS3 Protease","volume":"3","author":"Kumar","year":"2018","journal-title":"ACS Omega"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Xiong, Y., Cheng, F., Zhang, J., Su, H., Hu, H., Zou, Y., Li, M., and Xu, Y. (2022). Structure-based design of a novel inhibitor of the ZIKA virus NS2B\/NS3 protease. Bioorg. Chem., 128.","DOI":"10.1016\/j.bioorg.2022.106109"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"20322","DOI":"10.1039\/D2NJ01983C","article-title":"Fragment-based design of \u03b1-cyanoacrylates and \u03b1-cyanoacrylamides targeting Dengue and Zika NS2B\/NS3 proteases","volume":"46","author":"Vilela","year":"2022","journal-title":"New J. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/j.bbrc.2017.03.107","article-title":"Discovering key residues of dengue virus NS2b-NS3-protease: New binding sites for antiviral inhibitors design","volume":"492","author":"Robayo","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6555","DOI":"10.1021\/acs.jmedchem.1c01860","article-title":"Structure-Based Optimization and Characterization of Macrocyclic Zika Virus NS2B-NS3 Protease Inhibitors","volume":"65","author":"Huber","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6825","DOI":"10.1021\/acs.jcim.2c00596","article-title":"Discovery of New Zika Protease and Polymerase Inhibitors through the Open Science Collaboration Project OpenZika","volume":"62","author":"Mottin","year":"2022","journal-title":"J. Chem. Inf. Model."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Daina, A., Michielin, O., and Zoete, V. (2017). SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 7.","DOI":"10.1038\/srep42717"},{"key":"ref_46","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_47","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1038\/nsmb1073","article-title":"Structural basis for the activation of flaviviral NS3 proteases from dengue and West Nile virus","volume":"13","author":"Erbel","year":"2006","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s13321-016-0139-1","article-title":"AutoDock VinaXB: Implementation of XBSF, new empirical halogen bond scoring function, into AutoDock Vina","volume":"8","author":"Koebel","year":"2016","journal-title":"J. Cheminform."},{"key":"ref_49","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Mennucci, B., and Petersson, G.A. (2009). 75 Gaussian 09, Revision d. 01, Gaussian. Inc."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"17881","DOI":"10.1021\/acsomega.2c01188","article-title":"Discovery of Anilino-1,4-naphthoquinones as Potent EGFR Tyrosine Kinase Inhibitors: Synthesis, Biological Evaluation, and Comprehensive Molecular Modeling","volume":"7","author":"Mahalapbutr","year":"2022","journal-title":"ACS Omega"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"13644","DOI":"10.1021\/acs.jpcb.1c07060","article-title":"In Silico Elucidation of Potent Inhibitors and Rational Drug Design against SARS-CoV-2 Papain-like Protease","volume":"125","author":"Sanachai","year":"2021","journal-title":"J. Phys. Chem. B"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"118002","DOI":"10.1016\/j.molliq.2021.118002","article-title":"Molecular encapsulation of emodin with various \u03b2-cyclodextrin derivatives: A computational study","volume":"347","author":"Oo","year":"2022","journal-title":"J. Mol. Liq."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3696","DOI":"10.1021\/acs.jctc.5b00255","article-title":"ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB","volume":"11","author":"Maier","year":"2015","journal-title":"J. Chem. Theory Comput."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"116394","DOI":"10.1016\/j.molliq.2021.116394","article-title":"Molecular encapsulation of a key odor-active 2-acetyl-1-pyrroline in aromatic rice with \u03b2-cyclodextrin derivatives","volume":"337","author":"Mahalapbutr","year":"2021","journal-title":"J. Mol. Liq."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of simple potential functions for simulating liquid water","volume":"79","author":"Jorgensen","year":"1983","journal-title":"J. Chem. Phys."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"10089","DOI":"10.1063\/1.464397","article-title":"Particle mesh Ewald: An N\u00b7log(N) method for Ewald sums in large systems","volume":"98","author":"Darden","year":"1993","journal-title":"J. Chem. Phys."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/0021-9991(77)90098-5","article-title":"Numerical integration of the cartesian equations of motion of a system with constraints: Molecular dynamics of n-alkanes","volume":"23","author":"Ryckaert","year":"1977","journal-title":"J. Comput. Phys."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.1063\/1.448118","article-title":"Molecular dynamics with coupling to an external bath","volume":"81","author":"Berendsen","year":"1984","journal-title":"J. Chem. Phys."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"6363","DOI":"10.1063\/1.1667473","article-title":"Synchronization of trajectories in canonical molecular-dynamics simulations: Observation, explanation, and exploitation","volume":"120","author":"Uberuaga","year":"2004","journal-title":"J. Chem. Phys."},{"key":"ref_60","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_61","unstructured":"Case, D.A., Belfon, K.A.A., Ben-Shalom, I.Y., Brozell, S.R., Cerutti, D.S., Cheatham, T.E., Cruzeiro, V.W.D., Darden, T.A., Duke, R.E., and Giambasu, G. (2020). AMBER 2020, University of California."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1002\/1097-0282(2000)56:4<275::AID-BIP10024>3.0.CO;2-E","article-title":"Theory and applications of the generalized born solvation model in macromolecular simulations","volume":"56","author":"Tsui","year":"2000","journal-title":"Biopolymers"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Patigo, A., Hengphasatporn, K., Cao, V., Paunrat, W., Vijara, N., Chokmahasarn, T., Maitarad, P., Rungrotmongkol, T., Shigeta, Y., and Boonyasuppayakorn, S. (2022). Design, synthesis, in vitro, in silico, and SAR studies of flavone analogs towards anti-dengue activity. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-25836-5"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"105753","DOI":"10.1016\/j.antiviral.2023.105753","article-title":"A sulfonamide chalcone inhibited dengue virus with a potential target at the SAM-binding site of viral methyltransferase","volume":"220","author":"Cao","year":"2023","journal-title":"Antivir. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/23\/11762\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T05:13:53Z","timestamp":1764998033000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/23\/11762"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,4]]},"references-count":64,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["ijms262311762"],"URL":"https:\/\/doi.org\/10.3390\/ijms262311762","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,4]]}}}