{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T20:27:03Z","timestamp":1788121623634,"version":"build-2803163510"},"reference-count":57,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T00:00:00Z","timestamp":1741737600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Dengue Fever, a widespread mosquito-borne disease caused by the dengue virus (DENV), poses a major health threat in tropical and subtropical regions worldwide, resulting in millions of infections yearly. Severe cases of dengue fever have a mortality rate of around fifteen percent. Currently, there are no antiviral treatments for this disease and the only FDA-approved vaccine has been known to have adverse effects, especially in children. Thus, there is an urgent need for new therapeutics for Dengue fever. The largest issue with developing an antiviral treatment is that DENV has four serotypes that each differ slightly enough to pose problems with one compound inhibiting all four. This study addresses that challenge to some extent by focusing on in silico screening of potential hits targeting the envelope glycoprotein, which is relatively conserved across these four serotypes. Using pharmacophore screening and in silico evaluation of ligands, we identified compounds which could potentially have high affinity to the envelope glycoprotein for two of the four DENV serotypes. These in silico results were validated experimentally using bio-layer interferometry. These findings lay a foundation for in vitro analysis and hit-to-lead studies, advancing the development of antivirals that can inhibit multiple serotypes of the dengue virus.<\/jats:p>","DOI":"10.3390\/molecules30061268","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T07:31:42Z","timestamp":1741764702000},"page":"1268","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["In Silico Evaluation of Potential Hit Molecules Against Multiple Serotypes of Dengue Virus Envelope Glycoprotein"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8335-2121","authenticated-orcid":false,"given":"Aadhil","family":"Haq","sequence":"first","affiliation":[{"name":"Department of Biological and Agricultural Engineering, Texas A&M University, College Station, TX 77840, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8153-2388","authenticated-orcid":false,"given":"Samavath","family":"Mallawarachchi","sequence":"additional","affiliation":[{"name":"Department of Biological and Agricultural Engineering, Texas A&M University, College Station, TX 77840, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiden","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Biological and Agricultural Engineering, Texas A&M University, College Station, TX 77840, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leily","family":"Khaleghi","sequence":"additional","affiliation":[{"name":"Department of Biological and Agricultural Engineering, Texas A&M University, College Station, TX 77840, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7477-1679","authenticated-orcid":false,"given":"Lasan","family":"Manujitha","sequence":"additional","affiliation":[{"name":"Department of Biological and Agricultural Engineering, Texas A&M University, College Station, TX 77840, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7692-2170","authenticated-orcid":false,"given":"Sandun","family":"Fernando","sequence":"additional","affiliation":[{"name":"Department of Biological and Agricultural Engineering, Texas A&M University, College Station, TX 77840, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,12]]},"reference":[{"key":"ref_1","unstructured":"(2024, February 12). Dengue and Severe Dengue. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/dengue-and-severe-dengue."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1186\/s40249-021-00908-2","article-title":"Clinical predictors of severe dengue: A systematic review and meta-analysis","volume":"10","author":"Tsheten","year":"2021","journal-title":"Infect. Dis. Poverty"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nature12060","article-title":"The global distribution and burden of dengue","volume":"496","author":"Bhatt","year":"2013","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1136\/pgmj.2004.019638","article-title":"Dengue viral infections","volume":"80","author":"Malavige","year":"2004","journal-title":"Postgrad. Med. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s00284-020-02284-w","article-title":"Current Understanding of the Pathogenesis of Dengue Virus Infection","volume":"78","author":"Bhatt","year":"2021","journal-title":"Curr. Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"9","DOI":"10.7861\/clinmed.2021-0791","article-title":"Dengue infection: Global importance, immunopathology and management","volume":"22","author":"Kularatne","year":"2022","journal-title":"Clin. Med."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Lee, M.F., Wu, Y.S., and Poh, C.L. (2023). Molecular Mechanisms of Antiviral Agents against Dengue Virus. Viruses, 15.","DOI":"10.3390\/v15030705"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2831","DOI":"10.1007\/s11030-023-10716-5","article-title":"Repurposing of approved antivirals against dengue virus serotypes: An in silico and in vitro mechanistic study","volume":"28","author":"Rashmi","year":"2023","journal-title":"Mol. Divers."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.coviro.2020.07.009","article-title":"Recent advances in antiviral drug development towards dengue virus","volume":"43","author":"Troost","year":"2020","journal-title":"Curr. Opin. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Obi, J.O., Guti\u00e9rrez-Barbosa, H., Chua, J.V., and Deredge, D.J. (2021). Current Trends and Limitations in Dengue Antiviral Research. Trop. Med. Infect. Dis., 6.","DOI":"10.20944\/preprints202108.0364.v1"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"51","DOI":"10.2174\/1574891X10666150410153839","article-title":"Dengue Patients Treated with Doxycycline Showed Lower Mortality Associated to a Reduction in IL-6 and TNF Levels","volume":"10","author":"Fredeking","year":"2015","journal-title":"Recent Pat. Anti-Infect. Drug Discov."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1016\/S1473-3099(14)70730-3","article-title":"Efficacy and safety of celgosivir in patients with dengue fever (CELADEN): A phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial","volume":"14","author":"Low","year":"2014","journal-title":"Lancet Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1093\/cid\/civ949","article-title":"Lovastatin for the Treatment of Adult Patients With Dengue: A Randomized, Double-Blind, Placebo-Controlled Trial","volume":"62","author":"Whitehorn","year":"2016","journal-title":"Clin. Infect. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s40506-023-00263-w","article-title":"Dengue: Update on Clinically Relevant Therapeutic Strategies and Vaccines","volume":"15","author":"Rathore","year":"2023","journal-title":"Curr. Treat. Options Infect. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1056\/NEJMoa1506223","article-title":"Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease","volume":"373","author":"Hadinegoro","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1016\/S0140-6736(14)61060-6","article-title":"Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: A phase 3, randomised, observer-masked, placebo-controlled trial","volume":"384","author":"Capeding","year":"2014","journal-title":"Lancet"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1056\/NEJMoa1800820","article-title":"Effect of Dengue Serostatus on Dengue Vaccine Safety and Efficacy","volume":"379","author":"Sridhar","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/s41586-021-03990-6","article-title":"A pan-serotype dengue virus inhibitor targeting the NS3\u2013NS4B interaction","volume":"598","author":"Kaptein","year":"2021","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Hou, J., Ye, W., and Chen, J. (2022). Current Development and Challenges of Tetravalent Live-Attenuated Dengue Vaccines. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.840104"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"7769","DOI":"10.1128\/JVI.75.16.7769-7773.2001","article-title":"Monoclonal antibodies that bind to domain III of dengue virus E glycoprotein are the most efficient blockers of virus adsorption to Vero cells","volume":"75","author":"Crill","year":"2001","journal-title":"J. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.virol.2023.01.016","article-title":"Development of novel antiviral peptides against dengue serotypes 1\u20134","volume":"580","author":"Lee","year":"2023","journal-title":"Virology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4063","DOI":"10.1021\/acs.jmedchem.3c02336","article-title":"Discovery of JNJ-1802, a First-in-Class Pan-Serotype Dengue Virus NS4B Inhibitor","volume":"67","author":"Kesteleyn","year":"2024","journal-title":"J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.ejmech.2016.04.008","article-title":"Progress and prospects on DENV protease inhibitors","volume":"117","author":"Timiri","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Lee, J.-C., Chang, F.-R., Chen, S.-R., Wu, Y.-H., Hu, H.-C., Wu, Y.-C., Backlund, A., and Cheng, Y.-B. (2016). Anti-Dengue Virus Constituents from Formosan Zoanthid Palythoa mutuki. Mar. Drugs, 14.","DOI":"10.3390\/md14080151"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Lin, C.-S., Lu, C.-H., Lin, T.-H., Kiu, Y.-T., Kan, J.-Y., Chang, Y.-J., Hung, P.-Y., Koval\u2019skaya, A.V., Tsypyshev, D.O., and Tsypysheva, I.P. (2024). Inhibition of dengue viruses by N-methylcytisine thio derivatives through targeting viral envelope protein and NS2B-NS3 protease. Bioorganic Med. Chem. Lett., 99.","DOI":"10.1016\/j.bmcl.2024.129623"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1128\/AAC.01148-08","article-title":"A Small-Molecule Dengue Virus Entry Inhibitor","volume":"53","author":"Wang","year":"2009","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"516","DOI":"10.2174\/1386207319666160506123715","article-title":"An In-Silico Investigation of Phytochemicals as Antiviral Agents Against Dengue Fever","volume":"19","author":"Powers","year":"2016","journal-title":"Comb. Chem. High Throughput Screen."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Fleith, R.C., Lobo, F.P., dos Santos, P.F., Rocha, M.M., Bordignon, J., Strottmann, D.M., Patricio, D.O., Pavanelli, W.R., Lo Sarzi, M., and Santos, C.N.D. (2016). Genome-wide analyses reveal a highly conserved Dengue virus envelope peptide which is critical for virus viability and antigenic in humans. Sci. Rep., 6.","DOI":"10.1038\/srep36339"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Rathore, A.S., Sarker, A., and Gupta, R.D. (2019). Designing antibody against highly conserved region of dengue envelope protein by in silico screening of scFv mutant library. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0209576"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.antiviral.2018.04.018","article-title":"Peptides P4 and P7 derived from E protein inhibit entry of dengue virus serotype 2 via interacting with \u03b23 integrin","volume":"155","author":"Cui","year":"2018","journal-title":"Antivir. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5730","DOI":"10.1128\/JVI.00170-10","article-title":"In vitro reconstitution reveals key intermediate states of trimer formation by the dengue virus membrane fusion protein","volume":"84","author":"Liao","year":"2010","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"12707","DOI":"10.1021\/acsomega.1c07144","article-title":"ELIXIR-A: An Interactive Visualization Tool for Multi-Target Pharmacophore Refinement","volume":"7","author":"Wang","year":"2022","journal-title":"ACS Omega"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"W442","DOI":"10.1093\/nar\/gkw287","article-title":"Pharmit: Interactive exploration of chemical space","volume":"44","author":"Sunseri","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"102868","DOI":"10.1016\/j.jksus.2023.102868","article-title":"Malacitanolide, reissantin E and paclitaxel compounds as inhibitors of envelope, NS5 and NS2B\/NS3 target proteins of dengue virus: Computational docking and molecular dynamics simulations studies","volume":"35","author":"Ragavan","year":"2023","journal-title":"J. King Saud Univ.-Sci."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Yenamandra, S.P., Koo, C., Chiang, S., Lim, H.S.J., Yeo, Z.Y., Ng, L.C., and Hapuarachchi, H.C. (2021). Evolution, heterogeneity and global dispersal of cosmopolitan genotype of Dengue virus type 2. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-92783-y"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1186\/s40001-023-01454-3","article-title":"Dengue virus serotype did not contribute to clinical severity or mortality in Taiwan\u2019s largest dengue outbreak in 2015","volume":"28","author":"Tsai","year":"2023","journal-title":"Eur. J. Med. Res."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Dalpiaz, A., and Pavan, B. (2018). Nose-to-Brain Delivery of Antiviral Drugs: A Way to Overcome Their Active Efflux?. Pharmaceutics, 10.","DOI":"10.3390\/pharmaceutics10020039"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Calder\u00f3n-Pel\u00e1ez, M.-A., Velandia-Romero, M.L., Bastidas-Legarda, L.Y., Beltr\u00e1n, E.O., Camacho-Ortega, S.J., and Castellanos, J.E. (2019). Dengue Virus Infection of Blood\u2013Brain Barrier Cells: Consequences of Severe Disease. Front. Microbiol., 10.","DOI":"10.3389\/fmicb.2019.01435"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1080\/17425255.2022.2099837","article-title":"Strategies for enhancing the oral bioavailability of cannabinoids","volume":"18","author":"Domb","year":"2022","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3367","DOI":"10.3390\/nu5093367","article-title":"Flavonoid Bioavailability and Attempts for Bioavailability Enhancement","volume":"5","author":"Thilakarathna","year":"2013","journal-title":"Nutrients"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(96)00423-1","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"23","author":"Lipinski","year":"1997","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e14915","DOI":"10.7717\/peerj.14915","article-title":"Structure-based computational screening of 470 natural quercetin derivatives for identification of SARS-CoV-2 M(pro) inhibitor","volume":"11","author":"Zothantluanga","year":"2023","journal-title":"PeerJ"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3052","DOI":"10.1080\/07391102.2022.2045221","article-title":"In silico and in vitro evaluation of imatinib as an inhibitor for SARS-CoV-2","volume":"41","author":"Mulgaonkar","year":"2023","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_44","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_45","doi-asserted-by":"crossref","first-page":"9478","DOI":"10.1021\/acs.chemrev.9b00055","article-title":"End-Point Binding Free Energy Calculation with MM\/PBSA and MM\/GBSA: Strategies and Applications in Drug Design","volume":"119","author":"Wang","year":"2019","journal-title":"Chem. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Wang, H., Mulgaonkar, N., Mallawarachchi, S., Ramasamy, M., Padilla, C.S., Irigoyen, S., Coaker, G., Mandadi, K.K., and Fernando, S. (2022). Evaluation of Candidatus Liberibacter Asiaticus Efflux Pump Inhibition by Antimicrobial Peptides. Molecules, 27.","DOI":"10.3390\/molecules27248729"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"6052","DOI":"10.1016\/j.cell.2021.11.010","article-title":"The epitope arrangement on flavivirus particles contributes to Mab C10\u2019s extraordinary neutralization breadth across Zika and dengue viruses","volume":"184","author":"Sharma","year":"2021","journal-title":"Cell"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"eabg4084","DOI":"10.1126\/sciadv.abg4084","article-title":"Designed, highly expressing, thermostable dengue virus 2 envelope protein dimers elicit quaternary epitope antibodies","volume":"7","author":"Kudlacek","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1128\/JVI.79.2.1223-1231.2005","article-title":"Variable Surface Epitopes in the Crystal Structure of Dengue Virus Type 3 Envelope Glycoprotein","volume":"79","author":"Modis","year":"2005","journal-title":"J. Virol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Giordano, D., Biancaniello, C., Argenio, M.A., and Facchiano, A. (2022). Drug Design by Pharmacophore and Virtual Screening Approach. Pharmaceuticals, 15.","DOI":"10.3390\/ph15050646"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1021\/jm0306430","article-title":"Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy","volume":"47","author":"Friesner","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3099","DOI":"10.1021\/ci300367a","article-title":"admetSAR: A comprehensive source and free tool for assessment of chemical ADMET properties","volume":"52","author":"Cheng","year":"2012","journal-title":"J. Chem. Inf. Model."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1093\/bioinformatics\/bty707","article-title":"admetSAR 2.0: Web-service for prediction and optimization of chemical ADMET properties","volume":"35","author":"Yang","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"W513","DOI":"10.1093\/nar\/gkae303","article-title":"ProTox 3.0: A webserver for the prediction of toxicity of chemicals","volume":"52","author":"Banerjee","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"9206","DOI":"10.1021\/acsomega.1c05659","article-title":"Suppressing Nonspecific Binding in Biolayer Interferometry Experiments for Weak Ligand\u2013Analyte Interactions","volume":"7","author":"Dubrow","year":"2022","journal-title":"ACS Omega"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"198995","DOI":"10.1016\/j.virusres.2022.198995","article-title":"A new host-targeted antiviral cyclolignan (SAU-22.107) for Dengue Virus infection in cell cultures. Potential action mechanisms based on cell imaging","volume":"323","author":"Brand","year":"2022","journal-title":"Virus Res."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Orthwein, T., Huergo, L.F., Forchhammer, K., and Selim, K.A. (2021). Kinetic Analysis of a Protein-protein Complex to Determine its Dissociation Constant (KD) and the Effective Concentration (EC50) of an Interplaying Effector Molecule Using Bio-layer Interferometry. Bio-Protocol, 11.","DOI":"10.21769\/BioProtoc.4152"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/6\/1268\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:51:08Z","timestamp":1760028668000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/6\/1268"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,12]]},"references-count":57,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["molecules30061268"],"URL":"https:\/\/doi.org\/10.3390\/molecules30061268","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,12]]}}}