{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T02:14:35Z","timestamp":1783131275787,"version":"3.54.6"},"reference-count":52,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,15]],"date-time":"2022-07-15T00:00:00Z","timestamp":1657843200000},"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>Influenza virus infections continue to be a significant and recurrent public health problem. Although vaccine efficacy varies, regular immunisation is the most effective method for suppressing the influenza virus. Antiviral drugs are available for influenza, although two of the four FDA-approved antiviral treatments have resulted in significant drug resistance. Therefore, new treatments are being sought to reduce the burden of flu-related illness. The time-consuming development of treatments for new and re-emerging diseases such as influenza and the high failure rate are increasing concerns. In this context, we used an in silico-based drug repurposing method to repurpose FDA-approved drugs as potential therapies against the H7N9 virus. To find potential inhibitors, a total of 2568 drugs were screened. Promacta, tucatinib, and lurasidone were identified as promising hits in the DrugBank database. According to the calculations of MM-GBSA, tucatinib (\u221254.11 kcal\/mol) and Promacta (\u221256.20 kcal\/mol) occupied the active site of neuraminidase with a higher binding affinity than the standard drug peramivir (\u221249.09 kcal\/mol). Molecular dynamics (MD) simulation studies showed that the C-\u03b1 atom backbones of the complexes of tucatinib and Promacta neuraminidase were stable throughout the simulation period. According to ADME analysis, the hit compounds have a high gastrointestinal absorption (GI) and do not exhibit properties that allow them to cross the blood\u2013brain barrier (BBB). According to the in silico toxicity prediction, Promacta is not cardiotoxic, while lurasidone and tucatinib show only weak inhibition. Therefore, we propose to test these compounds experimentally against the influenza H7N9 virus. The investigation and validation of these potential H7N9 inhibitors would be beneficial in order to bring these compounds into clinical settings.<\/jats:p>","DOI":"10.3390\/molecules27144515","type":"journal-article","created":{"date-parts":[[2022,7,15]],"date-time":"2022-07-15T01:57:11Z","timestamp":1657850231000},"page":"4515","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["In Silico Drug Repurposing of FDA-Approved Drugs Highlighting Promacta as a Potential Inhibitor of H7N9 Influenza Virus"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3444-7073","authenticated-orcid":false,"given":"Sphamandla E.","family":"Mtambo","sequence":"first","affiliation":[{"name":"Drug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hezekiel M.","family":"Kumalo","sequence":"additional","affiliation":[{"name":"Drug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,15]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (WHO) (2021). Analysis of Recent Scientific Information on Avian Influenza A(H7N9) Virus, World Health Organization. Available online: https:\/\/www.who.int\/influenza\/human_animal_interface\/avian_influenza\/riskassessment_AH7N9_201702\/en\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1056\/NEJMoa1304459","article-title":"Human Infection with a Novel Avian-Origin Influenza A (H7N9) Virus","volume":"368","author":"Gao","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2277","DOI":"10.1056\/NEJMoa1305584","article-title":"Clinical Findings in 111 Cases of Influenza A (H7N9) Virus Infection","volume":"368","author":"Gao","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.15585\/mmwr.mm6549a2","article-title":"Assessing Change in Avian Influenza A(H7N9) Virus Infections During the Fourth Epidemic\u2014China, September 2015\u2013August 2016","volume":"65","author":"Xiang","year":"2016","journal-title":"MMWR. Morb. Mortal. Wkly. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/303041a0","article-title":"Structure of the catalytic and antigenic sites in influenza virus neuraminidase","volume":"303","author":"Colman","year":"1983","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Mtambo, S.E., Amoako, D.G., Somboro, A.M., Agoni, C., Lawal, M.M., Gumede, N.S., Khan, R.B., and Kumalo, H.M. (2021). Influenza Viruses: Harnessing the Crucial Role of the M2 Ion-Channel and Neuraminidase toward Inhibitor Design. Molecules, 26.","DOI":"10.3390\/molecules26040880"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/nature12392","article-title":"Characterization of H7N9 influenza A viruses isolated from humans","volume":"501","author":"Watanabe","year":"2013","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1038\/nature12379","article-title":"Biological features of novel avian influenza A (H7N9) virus","volume":"499","author":"Zhou","year":"2013","journal-title":"Nature"},{"key":"ref_9","first-page":"1486","article-title":"Glycan-Receptor Binding of the Influenza A Virus H7N9 Hemagglutinin","volume":"153","author":"Tharakaraman","year":"2013","journal-title":"NIH Public Access"},{"key":"ref_10","first-page":"63","article-title":"Receptor binding properties of the influenza virus hemagglutinin as a determinant of host range","volume":"385","author":"Xiong","year":"2014","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2339","DOI":"10.1056\/NEJMc1305865","article-title":"Serologic Study for Influenza A (H7N9) among High-Risk Groups in China","volume":"368","author":"Bai","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_12","first-page":"531","article-title":"Antiviral Drugs for Influenza and Other Respiratory Virus Infections|Elsevier Enhanced Reader","volume":"1","author":"Aoki","year":"2015","journal-title":"Mand. Douglas Bennett\u2019s Princ. Pract. Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.antiviral.2013.03.014","article-title":"Influenza virus resistance to neuraminidase inhibitors","volume":"98","author":"Samson","year":"2013","journal-title":"Antiviral Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.jinf.2017.04.001","article-title":"Human infections with recently-emerging highly pathogenic H7N9 avian influenza virus in China","volume":"75","author":"Zhang","year":"2017","journal-title":"J. Infect."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1056\/NEJMoa1304617","article-title":"Epidemiology of Human Infections with Avian Influenza A(H7N9) Virus in China","volume":"370","author":"Li","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2750","DOI":"10.1038\/s41467-020-16585-y","article-title":"Modeling mitigation of influenza epidemics by baloxavir","volume":"11","author":"Du","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1007\/s40261-018-0710-9","article-title":"Safety, Tolerability, and Pharmacokinetics of the Novel Anti-influenza Agent Baloxavir Marboxil in Healthy Adults: Phase I Study Findings","volume":"38","author":"Koshimichi","year":"2018","journal-title":"Clin. Drug Investig."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/nature05114","article-title":"The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design","volume":"443","author":"RJ","year":"2006","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/0022-2836(91)80068-6","article-title":"Three-dimensional Structure of the Negraminidase of Influenza Virus A\/Tokyo\/3\/67 at 2-2 A Resolution receptor","volume":"221","author":"Varghese","year":"1991","journal-title":"J. Mol. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1001\/jama.2020.1166","article-title":"Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009\u20132018","volume":"323","author":"Wouters","year":"2020","journal-title":"JAMA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1021\/cr300314q","article-title":"Integrated approach to structure-based enzymatic drug design: Molecular modeling, spectroscopy, and experimental bioactivity","volume":"114","author":"Honarparvar","year":"2014","journal-title":"Chem. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3296","DOI":"10.2174\/1568026618666180101163651","article-title":"Recent Updates on Computer-aided Drug Discovery: Time for a Paradigm Shift","volume":"17","author":"Usha","year":"2017","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Batool, M., Ahmad, B., and Choi, S. (2019). A Structure-Based Drug Discovery Paradigm. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20112783"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"343","DOI":"10.3389\/fchem.2020.00343","article-title":"Structure-Based Virtual Screening: From Classical to Artificial Intelligence","volume":"8","author":"Maia","year":"2020","journal-title":"Front. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s13321-019-0362-7","article-title":"DockRMSD: An open-source tool for atom mapping and RMSD calculation of symmetric molecules through graph isomorphism","volume":"11","author":"Bell","year":"2019","journal-title":"J. Cheminform."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7432","DOI":"10.1073\/pnas.102179699","article-title":"Evaluating conformational free energies: The colony energy and its application to the problem of loop prediction","volume":"99","author":"Xiang","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"128101","DOI":"10.1103\/PhysRevLett.126.128101","article-title":"Universal Relation between Instantaneous Diffusivity and Radius of Gyration of Proteins in Aqueous Solution","volume":"126","author":"Yamamoto","year":"2021","journal-title":"Phys. Rev. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1021\/jp9083635","article-title":"The Role of Non-Bonded Interactions in the Conformational Dynamics of Organophosphorous Hydrolase Adsorbed onto Functionalized Mesoporous Silica Surfaces","volume":"114","author":"Gomes","year":"2010","journal-title":"J. Phys. Chem. B"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1038\/jcbfm.2012.126","article-title":"Drug transport across the blood\u2013brain barrier","volume":"32","author":"Pardridge","year":"2012","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1615\/CritRevTherDrugCarrierSyst.2015011592","article-title":"Polymeric Drug-Delivery Systems: Role in P-gp Efflux System Inhibition","volume":"32","author":"Gupta","year":"2015","journal-title":"Crit. Rev. Ther. Drug Carrier Syst."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"27","DOI":"10.4137\/DTI.S12519","article-title":"P-glycoprotein Inhibition for Optimal Drug Delivery","volume":"7","author":"Amin","year":"2013","journal-title":"Drug Target Insights"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading","volume":"30","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_34","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_35","doi-asserted-by":"crossref","first-page":"D1074","DOI":"10.1093\/nar\/gkx1037","article-title":"DrugBank 5.0: A major update to the DrugBank database for 2018","volume":"46","author":"Wishart","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(00)00129-0","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"46","author":"Lipinski","year":"2001","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_37","unstructured":"Biovia, D.S. (2016). Discovery Studio Modeling Environment, Release 2020, Dassault Systems. Available online: https:\/\/www.3ds.com\/."},{"key":"ref_38","unstructured":"Schr\u00f6dinger, L., and DeLano, W. (2022, April 25). PyMol 2021. Available online: https:\/\/pymol.org\/pymol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"W257","DOI":"10.1093\/nar\/gky318","article-title":"ProTox-II: A webserver for the prediction of toxicity of chemicals","volume":"46","author":"Banerjee","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1002\/minf.201500040","article-title":"Pred-hERG: A Novel web-Accessible Computational Tool for Predicting Cardiac Toxicity","volume":"34","author":"Braga","year":"2015","journal-title":"Mol. Inform."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Ben-shalom, I.Y., Lin, C., Radak, B.K., Sherman, W., and Gilson, M.K. (2021). Fast Equilibration of Water between Buried Sites and Bulk by MD with Parallel Monte Carlo Water Moves on GPUs. J. Chem. Theory. Comput., 7366\u20137372.","DOI":"10.1021\/acs.jctc.1c00867"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"129907","DOI":"10.1016\/j.bbagen.2021.129907","article-title":"Cross-reactivity of two human IL-6 family cytokines OSM and LIF explored by protein-protein docking and molecular dynamics simulation","volume":"1865","author":"Du","year":"2021","journal-title":"Biochim. Biophys. Acta Gen. Subj."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Fakhar, Z., Hejazi, L., Tabatabai, S.A., and Munro, O.Q. (2021). Discovery of novel heterocyclic amide-based inhibitors: An integrative in-silico approach to targeting soluble epoxide hydrolase. J. Biomol. Struct. Dyn., 1\u201315.","DOI":"10.1080\/07391102.2021.1894987"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3567","DOI":"10.1016\/j.apsb.2021.07.012","article-title":"Discovery of a small molecule inhibitor of cullin neddylation that triggers ER stress to induce autophagy","volume":"11","author":"Li","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3350","DOI":"10.1039\/D0SC06134D","article-title":"Hierarchical dynamics in allostery following ATP hydrolysis monitored by single molecule FRET measurements and MD simulations","volume":"12","author":"Wolf","year":"2021","journal-title":"Chem. Sci."},{"key":"ref_47","first-page":"9679","article-title":"In-silico Analysis and Molecular Dynamics Simulations of Lysozyme by GROMACS 2020.2","volume":"25","author":"Panwar","year":"2021","journal-title":"Ann. Rom. Soc. Cell Biol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Jin, T., Patel, S.J., and Lehn, R.C. (2021). Van Molecular simulations of lipid membrane partitioning and translocation by bacterial quorum sensing modulators. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0246187"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1021\/ar000033j","article-title":"Calculating structures and free energies of complex molecules: Combining molecular mechanics and continuum models","volume":"33","author":"Kollman","year":"2000","journal-title":"Acc. Chem. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1023\/A:1008763014207","article-title":"Combined molecular mechanical and continuum solvent approach (MM-PBSA\/GBSA) to predict ligand binding","volume":"18","author":"Massova","year":"2000","journal-title":"Perspect. Drug Discov. Des."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1021\/ci100275a","article-title":"Assessing the performance of the MM\/PBSA and MM\/GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics simulations","volume":"51","author":"Hou","year":"2011","journal-title":"J. Chem. Inf. Model."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"8408","DOI":"10.1021\/jp404160y","article-title":"Assessing the performance of MM\/PBSA and MM\/GBSA methods. 3. The impact of force fields and ligand charge models","volume":"117","author":"Xu","year":"2013","journal-title":"J. Phys. Chem. B"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/14\/4515\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:50:53Z","timestamp":1760140253000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/14\/4515"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,15]]},"references-count":52,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["molecules27144515"],"URL":"https:\/\/doi.org\/10.3390\/molecules27144515","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,15]]}}}