{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T01:21:11Z","timestamp":1782177671668,"version":"3.54.5"},"reference-count":56,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,8,20]],"date-time":"2022-08-20T00:00:00Z","timestamp":1660953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Dengue virus (DENV) is the causative agent of DENV infection. To tackle DENV infection, the development of therapeutic molecules as direct-acting antivirals (DAAs) has been demonstrated as a truly effective approach. Among various DENV drug targets, non-structural protein 5 (NS5)\u2014a highly conserved protein among the family Flaviviridae\u2014carries the RNA-dependent RNA polymerase (DENVRdRp) domain at the C-terminal, and its \u201cN-pocket\u201d allosteric site is widely considered for anti-DENV drug development. Therefore, in this study, we developed a pharmacophore model by utilising 41 known inhibitors of the DENVRdRp domain, and performed model screening against the FDA\u2019s approved drug database for drug repurposing against DENVRdRp. Herein, drugs complying with the pharmacophore hypothesis were further processed through standard-precision (SP) and extra-precision (XP) docking scores (DSs) and binding pose refinement based on MM\/GBSA binding energy (BE) calculations. This resulted in the identification of four potential potent drugs: (i) desmopressin (DS: \u221210.52, BE: \u221269.77 kcal\/mol), (ii) rutin (DS: \u221213.43, BE: \u221267.06 kcal\/mol), (iii) lypressin (DS: \u22129.84, BE: \u221267.65 kcal\/mol), and (iv) lanreotide (DS: \u22128.72, BE: \u221264.7 kcal\/mol). The selected drugs exhibited relevant interactions with the allosteric N-pocket of DENVRdRp, including priming-loop and entry-point residues (i.e., R729, R737, K800, and E802). Furthermore, 100 ns explicit-solvent molecular dynamics simulations and end-point binding free energy assessments support the considerable stability and free energy of the selected drugs in the targeted allosteric pocket of DENVRdRp. Hence, these four drugs, repurposed as potent inhibitors of the allosteric site of DENVRdRp, are recommended for further validation using experimental assays.<\/jats:p>","DOI":"10.3390\/v14081827","type":"journal-article","created":{"date-parts":[[2022,8,22]],"date-time":"2022-08-22T01:56:40Z","timestamp":1661133400000},"page":"1827","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Pharmacophore-Model-Based Drug Repurposing for the Identification of the Potential Inhibitors Targeting the Allosteric Site in Dengue Virus NS5 RNA-Dependent RNA Polymerase"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9186-6242","authenticated-orcid":false,"given":"Sanjay","family":"Kumar","sequence":"first","affiliation":[{"name":"School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India"},{"name":"Center for Bioinformatics, Computational and Systems Biology, Pathfinder Research and Training Foundation, Greater Noida 201308, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leena","family":"Bajrai","sequence":"additional","affiliation":[{"name":"Special Infectious Agents Unit\u2014BSL3, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21362, Saudi Arabia"},{"name":"Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah 21362, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arwa","family":"Faizo","sequence":"additional","affiliation":[{"name":"Special Infectious Agents Unit\u2014BSL3, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21362, Saudi Arabia"},{"name":"Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21362, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiah","family":"Khateb","sequence":"additional","affiliation":[{"name":"Special Infectious Agents Unit\u2014BSL3, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21362, Saudi Arabia"},{"name":"Medical Laboratory Technology Department, College of Applied Medical Sciences, Taibah University, Medina 42353, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5614-7229","authenticated-orcid":false,"given":"Areej","family":"Alkhaldy","sequence":"additional","affiliation":[{"name":"Special Infectious Agents Unit\u2014BSL3, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21362, Saudi Arabia"},{"name":"Clinical Nutrition Department, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0071-089X","authenticated-orcid":false,"given":"Rashmi","family":"Rana","sequence":"additional","affiliation":[{"name":"Department of Research, Sir Ganga Ram Hospital, New Delhi 110060, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1736-181X","authenticated-orcid":false,"given":"Esam","family":"Azhar","sequence":"additional","affiliation":[{"name":"Special Infectious Agents Unit\u2014BSL3, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21362, Saudi Arabia"},{"name":"Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21362, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0767-1328","authenticated-orcid":false,"given":"Vivek","family":"Dwivedi","sequence":"additional","affiliation":[{"name":"Center for Bioinformatics, Computational and Systems Biology, Pathfinder Research and Training Foundation, Greater Noida 201308, India"},{"name":"Bioinformatics Research Division, Quanta Calculus Pvt. 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Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/nrd.2017.33","article-title":"Broad-spectrum agents for flaviviral infections: Dengue, zika and beyond","volume":"16","author":"Boldescu","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_6","first-page":"319","article-title":"Dengue antiviral development: A continuing journey","volume":"Volume 1062","author":"Hilgenfeld","year":"2018","journal-title":"Dengue and Zika: Control and Antiviral Treatment Strategies"},{"key":"ref_7","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_8","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1111\/j.1600-0854.2005.00339.x","article-title":"Wrapping things up about virus RNA replication","volume":"6","author":"Mackenzie","year":"2005","journal-title":"Traffic"},{"key":"ref_9","first-page":"139","article-title":"Viral RNA replication in association with cellular membranes","volume":"285","author":"Salonen","year":"2005","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"39926","DOI":"10.1074\/jbc.M104248200","article-title":"De novo synthesis of RNA by the dengue virus RNA-dependent RNA polymerase exhibits temperature dependence at the initiation but not elongation phase","volume":"276","author":"Ackermann","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4386","DOI":"10.2174\/1381612826666200523174753","article-title":"A review on the progress and prospects of dengue drug discovery targeting NS5 RNA- dependent RNA polymerase","volume":"26","author":"Maddipati","year":"2020","journal-title":"Curr. Pharm. Des."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Zhao, Y., Soh, T.S., Zheng, J., Chan, K.W.K., Phoo, W.W., Lee, C.C., Tay, M.Y.F., Swaminathan, K., Cornvik, T.C., and Lim, S.P. (2015). A crystal structure of the dengue virus NS5 protein reveals a novel inter-domain interface essential for protein flexibility and virus replication. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1004682"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2067","DOI":"10.1074\/jbc.M110.162685","article-title":"Characterization of the elongation complex of dengue virus RNA polymerase: Assembly, kinetics of nucleotide incorporation, and fidelity","volume":"286","author":"Jin","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Lim, S.P., Noble, C.G., Seh, C.C., Soh, T.S., El Sahili, A., Chan, G.K.Y., Lescar, J., Arora, R., Benson, T., and Nilar, S. (2016). Potent allosteric dengue virus NS5 polymerase inhibitors: Mechanism of action and resistance profiling. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005737"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3935","DOI":"10.1021\/acs.jmedchem.6b00143","article-title":"Discovery of potent non-nucleoside inhibitors of dengue viral RNA-dependent RNA polymerase from a fragment hit using structure-based drug design","volume":"59","author":"Yokokawa","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"8541","DOI":"10.1074\/jbc.M115.710731","article-title":"A conserved pocket in the dengue virus polymerase identified through fragment-based screening","volume":"291","author":"Noble","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.virusres.2016.05.029","article-title":"Computational predictions suggest that structural similarity in viral polymerases may lead to comparable allosteric binding sites","volume":"222","author":"Brown","year":"2016","journal-title":"Virus Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/nature13027","article-title":"Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430","volume":"508","author":"Warren","year":"2014","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.antiviral.2009.02.198","article-title":"T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections","volume":"82","author":"Furuta","year":"2009","journal-title":"Antivir. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1038\/82191","article-title":"The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen","volume":"6","author":"Crotty","year":"2000","journal-title":"Nat. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"113201","DOI":"10.1016\/j.ejmech.2021.113201","article-title":"RNA-dependent RNA polymerase (RdRp) inhibitors: The current landscape and repurposing for the COVID-19 pandemic","volume":"213","author":"Tian","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2481","DOI":"10.1021\/jm201384j","article-title":"Nucleoside, Nucleotide, and Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B RNA-Dependent RNA-Polymerase","volume":"55","author":"Sofia","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Chen, H., Zhang, Z., and Zhang, J. (2022). In silico drug repositioning based on integrated drug targets and canonical correlation analysis. BMC Med. Genom., 15.","DOI":"10.1186\/s12920-022-01203-1"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"997","DOI":"10.2741\/4630","article-title":"Drug repurposing approaches to fight dengue virus infection and related diseases","volume":"23","author":"Botta","year":"2018","journal-title":"Front. Biosci. Landmark Ed."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"S96","DOI":"10.1093\/infdis\/jiw423","article-title":"Current status of dengue therapeutics research and development","volume":"215","author":"Low","year":"2017","journal-title":"J. Infect. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.antiviral.2014.09.007","article-title":"Antiviral activity of lanatoside C against dengue virus infection","volume":"111","author":"Cheung","year":"2014","journal-title":"Antivir. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"104668","DOI":"10.1016\/j.antiviral.2019.104668","article-title":"In silico drug repurposing for the identification of potential candidate molecules against arboviruses infection","volume":"173","author":"Espinosa","year":"2020","journal-title":"Antivir. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"10136","DOI":"10.1038\/s41598-021-89171-x","article-title":"Application of multiple omics and network projection analyses to drug repositioning for pathogenic mosquito-borne viruses","volume":"11","author":"Amemiya","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Pathak, N., Lai, M.-L., Chen, W.-Y., Hsieh, B.-W., Yu, G.-Y., and Yang, J.-M. (2017). Pharmacophore anchor models of flaviviral NS3 proteases lead to drug repurposing for DENV infection. BMC Bioinform., 18.","DOI":"10.1186\/s12859-017-1957-5"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The protein data bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_31","unstructured":"(2018). Schr\u00f6dinger Release 2018-3: Protein Preparation Wizard, Epik, Schr\u00f6dinger, LLC."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1007\/s10822-010-9349-1","article-title":"Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution","volume":"24","author":"Greenwood","year":"2010","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1007\/s10822-007-9133-z","article-title":"Epik: A software program for PK a prediction and protonation state generation for drug-like molecules","volume":"21","author":"Shelley","year":"2007","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"bbaa098","DOI":"10.1093\/bib\/bbaa098","article-title":"DenvInD: Dengue virus inhibitors database for clinical and molecular research","volume":"22","author":"Dwivedi","year":"2021","journal-title":"Brief. Bioinform."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"D1202","DOI":"10.1093\/nar\/gkv951","article-title":"PubChem substance and compound databases","volume":"44","author":"Kim","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_36","unstructured":"(2018). Schr\u00f6dinger Release 2018-3: LigPrep, Schr\u00f6dinger, LLC."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"80ps16","DOI":"10.1126\/scitranslmed.3001862","article-title":"The NCGC pharmaceutical collection: A comprehensive resource of clinically approved drugs enabling repurposing and chemical genomics","volume":"3","author":"Huang","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1111\/j.1747-0285.2006.00384.x","article-title":"PHASE: A novel approach to pharmacophore modeling and 3D database searching","volume":"67","author":"Dixon","year":"2006","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1007\/s10822-006-9087-6","article-title":"PHASE: A new engine for pharmacophore perception, 3D QSAR model development, and 3D database screening: 1. methodology and preliminary results","volume":"20","author":"Dixon","year":"2006","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_40","unstructured":"(2021). Schr\u00f6dinger Release 2021-4: Phase, Schr\u00f6dinger, LLC."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6177","DOI":"10.1021\/jm051256o","article-title":"Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein\u2212ligand complexes","volume":"49","author":"Friesner","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_42","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_43","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1021\/jm030644s","article-title":"Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening","volume":"47","author":"Halgren","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_44","unstructured":"(2018). Schr\u00f6dinger Release 2018-3: Glide, Schr\u00f6dinger, LLC."},{"key":"ref_45","unstructured":"(2018). Schr\u00f6dinger Release 2018-3: Prime, Schr\u00f6dinger, LLC."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2794","DOI":"10.1002\/prot.23106","article-title":"The VSGB 2.0 model: A next generation energy model for high resolution protein structure modeling","volume":"79","author":"Li","year":"2011","journal-title":"Proteins"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Bowers, K.J., Chow, D.E., Xu, H., Dror, R.O., Eastwood, M.P., Gregersen, B.A., Klepeis, J.L., Kolossvary, I., Moraes, M.A., and Sacerdoti, F.D. (2006, January 11\u201317). Scalable algorithms for molecular dynamics simulations on commodity clusters. Proceedings of the 2006 ACM\/IEEE Conference on Supercomputing (SC\u201906), Tampa, FL, USA.","DOI":"10.1145\/1188455.1188544"},{"key":"ref_48","unstructured":"(2020). Schr\u00f6dinger Release 2020-4: Desmond Molecular Dynamics System, Schr\u00f6dinger. Maestro-Desmond Interoperability Tools."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"F1053","DOI":"10.1152\/ajprenal.00114.2004","article-title":"Altered expression of COX-1, COX-2, and MPGES in rats with nephrogenic and central diabetes insipidus","volume":"288","author":"Kotnik","year":"2005","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4644","DOI":"10.1021\/jf104786t","article-title":"Quercetin and rutin reduced the bioavailability of cyclosporine from neoral, an immunosuppressant, through activating P-glycoprotein and CYP 3A4","volume":"59","author":"Yu","year":"2011","journal-title":"J. Agric. Food Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1124\/mol.57.3.634","article-title":"Transport function and hepatocellular localization of Mrp6 in rat liver","volume":"57","author":"Madon","year":"2000","journal-title":"Mol. Pharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"51","DOI":"10.2165\/0003088-200948010-00004","article-title":"Population pharmacokinetic analysis of lanreotide autogel in healthy subjects: Evidence for injection interval of up to 2 months","volume":"48","author":"Peraire","year":"2009","journal-title":"Clin. Pharmacokinet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1021\/np300059n","article-title":"Flacourtosides A-F, phenolic glycosides isolated from Flacourtia ramontchi","volume":"75","author":"Bourjot","year":"2012","journal-title":"J. Nat. Prod."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4964","DOI":"10.1021\/acs.jmedchem.5b00108","article-title":"Discovery of Multitarget Antivirals Acting on Both the Dengue Virus NS5-NS3 Interaction and the Host Src\/Fyn Kinases","volume":"58","author":"Vincetti","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2446","DOI":"10.1021\/np200715v","article-title":"Alkylated flavanones from the bark of Cryptocarya chartacea as dengue virus NS5 polymerase inhibitors","volume":"74","author":"Allard","year":"2011","journal-title":"J. Nat. Prod."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.ejmech.2014.10.010","article-title":"A perspective on targeting non-structural proteins to combat neglected tropical diseases: Dengue, West Nile and Chikungunya viruses","volume":"87","author":"Bhakat","year":"2014","journal-title":"Eur. J. Med. Chem."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/8\/1827\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:12:52Z","timestamp":1760141572000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/8\/1827"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,20]]},"references-count":56,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["v14081827"],"URL":"https:\/\/doi.org\/10.3390\/v14081827","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,20]]}}}