{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:39Z","timestamp":1787028459215,"version":"build-2736575974"},"reference-count":85,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,22]],"date-time":"2021-08-22T00:00:00Z","timestamp":1629590400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sandooq Al Watan","award":["13300"],"award-info":[{"award-number":["13300"]}]},{"DOI":"10.13039\/100016714","name":"University of Sharjah","doi-asserted-by":"publisher","award":["1300"],"award-info":[{"award-number":["1300"]}],"id":[{"id":"10.13039\/100016714","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Unfortunately, COVID-19 is still a threat to humankind and has a dramatic impact on human health, social life, the world economy, and food security. With the limited number of suggested therapies under clinical trials, the discovery of novel therapeutic agents is essential. Here, a previously identified anti-SARS-CoV-2 compound named Compound 13 (1,2,5-Oxadiazole-3-carboximidic acid, 4,4\u2032-(methylenediimino) bis,bis[[(2-hydroxyphenyl)methylene]hydrazide) was subjected to an iterated virtual screening against SARS-CoV-2 Mpro using a combination of Ligand Designer and PathFinder. PathFinder, a computational reaction enumeration tool, was used for the rapid generation of enumerated structures via default reaction library. Ligand designer was employed for the computerized lead optimization and selection of the best structural modification that resulted in a favorable ligand\u2013protein complex. The obtained compounds that showed the best binding to Mpro were re-screened against TMPRSS2, leading to the identification of 20 shared compounds. The compounds were further visually inspected, which resulted in the identification of five shared compounds M1\u20135 with dual binding affinity. In vitro evaluation and enzyme inhibition assay indicated that M3, an analogue of Compound 13 afforded by replacing the phenolic moiety with pyridinyl, possesses an improved antiviral activity and safety. M3 displayed in vitro antiviral activity with IC50 0.016 \u00b5M and Mpro inhibition activity with IC50 0.013 \u00b5M, 7-fold more potent than the parent Compound 13 and potent than the antivirals drugs that are currently under clinical trials. Moreover, M3 showed potent activity against human TMPRSS2 and furin enzymes with IC50 0.05, and 0.08 \u00b5M, respectively. Molecular docking, WaterMap analysis, molecular dynamics simulation, and R-group analysis confirmed the superiority of the binding fit to M3 with the target enzymes. WaterMap analysis calculated the thermodynamic properties of the hydration site in the binding pocket that significantly affects the biological activity. Loading M3 on zinc oxide nanoparticles (ZnO NPs) increased the antiviral activity of the compound 1.5-fold, while maintaining a higher safety profile. In conclusion, lead optimized discovery following an iterated virtual screening in association with molecular docking and biological evaluation revealed a novel compound named M3 with promising dual activity against SARS-CoV-2. The compound deserves further investigation for potential clinical-based studies.<\/jats:p>","DOI":"10.3390\/ijms22169057","type":"journal-article","created":{"date-parts":[[2021,8,22]],"date-time":"2021-08-22T21:47:52Z","timestamp":1629668872000},"page":"9057","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Iterated Virtual Screening-Assisted Antiviral and Enzyme Inhibition Assays Reveal the Discovery of Novel Promising Anti-SARS-CoV-2 with Dual Activity"],"prefix":"10.3390","volume":"22","author":[{"given":"Rania","family":"Hamdy","sequence":"first","affiliation":[{"name":"Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates"},{"name":"Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bahgat","family":"Fayed","sequence":"additional","affiliation":[{"name":"Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates"},{"name":"Chemistry of Natural and Microbial Product Department, National Research Centre, Cairo 12622, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2878-5714","authenticated-orcid":false,"given":"Ahmed","family":"Mostafa","sequence":"additional","affiliation":[{"name":"Centre of Scientific Excellence for Influenza Viruses, National Research Centre, Giza 12622, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noura M. Abo","family":"Shama","sequence":"additional","affiliation":[{"name":"Centre of Scientific Excellence for Influenza Viruses, National Research Centre, Giza 12622, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara Hussein","family":"Mahmoud","sequence":"additional","affiliation":[{"name":"Centre of Scientific Excellence for Influenza Viruses, National Research Centre, Giza 12622, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1895-8562","authenticated-orcid":false,"given":"Chetan Hasmukh","family":"Mehta","sequence":"additional","affiliation":[{"name":"Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0508-1394","authenticated-orcid":false,"given":"Yogendra","family":"Nayak","sequence":"additional","affiliation":[{"name":"Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7691-615X","authenticated-orcid":false,"given":"Sameh S.","family":"M. Soliman","sequence":"additional","affiliation":[{"name":"Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates"},{"name":"College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"105924","DOI":"10.1016\/j.ijantimicag.2020.105924","article-title":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges","volume":"55","author":"Lai","year":"2020","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/s41418-020-00720-9","article-title":"COVID-19 vaccines: Where we stand and challenges ahead","volume":"28","author":"Forni","year":"2021","journal-title":"Cell Death Differ."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41541-021-00292-w","article-title":"SARS-CoV-2 vaccines strategies: A comprehensive review of phase 3 candidates","volume":"6","author":"Kyriakidis","year":"2021","journal-title":"NPJ Vaccines"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"100094","DOI":"10.1016\/j.lanepe.2021.100094","article-title":"Getting hands on a drug for Covid-19: Inhaled and intranasal niclosamide","volume":"4","author":"Kunzelmann","year":"2021","journal-title":"Lancet Reg. Health Eur."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"eabe0751","DOI":"10.1126\/sciadv.abe0751","article-title":"Structure and inhibition of the SARS-CoV-2 main protease reveal strategy for developing dual inhibitors against Mpro and cathepsin L","volume":"6","author":"Sacco","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1016\/S0140-6736(20)31022-9","article-title":"Remdesivir in adults with severe COVID-19: A randomised, double-blind, placebo-controlled, multicentre trial","volume":"395","author":"Wang","year":"2020","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e02479-20","DOI":"10.1128\/AAC.02479-20","article-title":"AT-527, a double prodrug of a guanosine nucleotide analog, is a potent inhibitor of SARS-CoV-2 in vitro and a promising oral antiviral for treatment of COVID-19","volume":"65","author":"Good","year":"2021","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-021-21992-w","article-title":"Favipiravir antiviral efficacy against SARS-CoV-2 in a hamster model","volume":"12","author":"Driouich","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/s41586-021-03312-w","article-title":"SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801","volume":"591","author":"Wahl","year":"2021","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.coviro.2021.04.006","article-title":"Considerations for the discovery and development of 3-chymotrypsin-like cysteine protease inhibitors targeting SARS-CoV-2 infection","volume":"49","author":"Vandyck","year":"2021","journal-title":"Curr. Opin. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1016\/S0140-6736(21)00370-6","article-title":"SARS-CoV-2 variants and ending the COVID-19 pandemic","volume":"397","author":"Fontanet","year":"2021","journal-title":"Lancet"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"128099","DOI":"10.1016\/j.bmcl.2021.128099","article-title":"Promising anti-SARS-CoV-2 drugs by effective dual targeting against the viral and host proteases","volume":"43","author":"Elseginy","year":"2021","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2018\/1062562","article-title":"The advancing of zinc oxide nanoparticles for biomedical applications","volume":"2018","author":"Jiang","year":"2018","journal-title":"Bioinorg. Chem. Appl."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7149","DOI":"10.2147\/OTT.S119428","article-title":"BRAF inhibitors and radiotherapy for melanoma brain metastases: Potential advantages and disadvantages of combination therapy","volume":"9","author":"Chowdhary","year":"2016","journal-title":"OncoTargets Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.jash.2010.03.001","article-title":"Combination therapy in hypertension","volume":"4","author":"Gradman","year":"2010","journal-title":"J. Am. Soc. Hypertens."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1039\/C8TB03266A","article-title":"A dual-inhibitor system for the effective antifibrillation of A\u03b240 peptides by biodegradable EGCG\u2013Fe(iii)\/PVP nanoparticles","volume":"7","author":"Liu","year":"2019","journal-title":"J. Mater. Chem. B"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1111\/j.1747-0285.2010.00981.x","article-title":"Structure-activity relationships (SAR) research of thiourea derivatives as dual inhibitors targeting both HIV-1 capsid and human cyclophilin A","volume":"76","author":"Chen","year":"2010","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6353","DOI":"10.1039\/C9CC02189B","article-title":"A dual-functional molecular strategy for in situ suppressing and visualizing of neuraminidase in aqueous solution using iridium (iii) complexes","volume":"55","author":"Wu","year":"2019","journal-title":"Chem. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1916","DOI":"10.1039\/C5MD00365B","article-title":"Multi-drug delivery nanocarriers for combination therapy","volume":"6","author":"Gadde","year":"2015","journal-title":"MedChemComm"},{"key":"ref_20","unstructured":"World Health Organization (2021, January 16). WHO Coronavirus Disease (COVID-19) Dashboard. Available online: https:\/\/covid19.who.int\/."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e00872-20","DOI":"10.1128\/AAC.00872-20","article-title":"Discovery of M protease inhibitors encoded by SARS-CoV-2","volume":"64","author":"Hung","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_22","unstructured":"Corum, J., Grady, D., Wee, S.-L., and Zimmer, C. (The New York Times, 2020). Coronavirus vaccine tracker, The New York Times."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1002\/hbe2.237","article-title":"A critical review of emerging technologies for tackling COVID-19 pandemic","volume":"3","author":"Mbunge","year":"2021","journal-title":"Hum. Behav. Emerg."},{"key":"ref_24","first-page":"61","article-title":"Off-label use of chloroquine and hydroxychloroquine for COVID-19 treatment in Africa against WHO recommendation","volume":"11","author":"Belayneh","year":"2020","journal-title":"Res. Rep. Trop. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1021\/acscentsci.0c00489","article-title":"Remdesivir: A review of its discovery and development leading to emergency use authorization for treatment of COVID-19","volume":"6","author":"Eastman","year":"2020","journal-title":"ACS Cent. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1016\/j.eng.2020.03.007","article-title":"Experimental treatment with favipiravir for COVID-19: An open-label control study","volume":"6","author":"Cai","year":"2020","journal-title":"Engineering"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1016\/S0140-6736(20)32013-4","article-title":"Lopinavir\u2013ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): A randomised, controlled, open-label, platform trial","volume":"396","author":"Horby","year":"2020","journal-title":"The Lancet"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ganesh, R., Philpot, L.M., Bierle, D.M., Anderson, R.J., Arndt, L.L., Arndt, R.F., Culbertson, T.L., Destro Borgen, M.J., Hanson, S.N., and Kennedy, B.D. (2021). Real-World Clinical Outcomes of Bamlanivimab and Casirivimab-Imdevimab among High-Risk Patients with Mild to Moderate Coronavirus Disease 2019. J. Infect. Dis., jiab377.","DOI":"10.1093\/infdis\/jiab377"},{"key":"ref_29","first-page":"49","article-title":"An EUA for Bamlanivimab and Etesevimab for COVID-19","volume":"63","author":"Orders","year":"2021","journal-title":"Med. Lett. Drugs Ther."},{"key":"ref_30","first-page":"97","article-title":"An EUA for Sotrovimab for Treatment of COVID-19","volume":"63","author":"Orders","year":"2021","journal-title":"Med. Lett. Drugs Ther."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Ramos-Guzm\u00e1n, C.A., Ruiz-Pern\u00eda, J.J., and Tu\u00f1\u00f3n, I. (2021). Computational simulations on the binding and reactivity of a nitrile inhibitor of the SARS-CoV-2 main protease. ChemComm.","DOI":"10.33774\/chemrxiv-2021-tndbs"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.3389\/fimmu.2020.01664","article-title":"Identification of SARS-CoV-2 cell entry inhibitors by drug repurposing using in silico structure-based virtual screening approach","volume":"11","author":"Choudhary","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1038\/s41586-020-2665-2","article-title":"Structures and distributions of SARS-CoV-2 spike proteins on intact virions","volume":"588","author":"Ke","year":"2020","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Jaiswal, G., and Kumar, V. (2020). In-silico design of a potential inhibitor of SARS-CoV-2 S protein. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0240004"},{"key":"ref_35","first-page":"429","article-title":"In silico screening of natural compounds as potential inhibitors of SARS-CoV-2 main protease and spike RBD: Targets for COVID-19","volume":"7","author":"Teli","year":"2020","journal-title":"Front. Mol. Biosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1007\/s11655-020-3427-6","article-title":"In silico screening of potential spike glycoprotein inhibitors of SARS-CoV-2 with drug repurposing strategy","volume":"26","author":"Wei","year":"2020","journal-title":"Chin. J. Integr. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/s41422-020-0282-0","article-title":"Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro","volume":"30","author":"Wang","year":"2020","journal-title":"Cell Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e00819-20","DOI":"10.1128\/AAC.00819-20","article-title":"Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs","volume":"64","author":"Jeon","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Murgolo, N., Therien, A.G., Howell, B., Klein, D., Koeplinger, K., Lieberman, L.A., Adam, G.C., Flynn, J., McKenna, P., and Swaminathan, G. (2021). SARS-CoV-2 tropism, entry, replication, and propagation: Considerations for drug discovery and development. PLoS Pathog., 17.","DOI":"10.1371\/journal.ppat.1009225"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1866","DOI":"10.1056\/NEJMc2100362","article-title":"New SARS-CoV-2 variants\u2014Clinical, public health, and vaccine implications","volume":"384","year":"2021","journal-title":"N. Eng. J. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e202000786","DOI":"10.26508\/lsa.202000786","article-title":"TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells","volume":"3","author":"Bestle","year":"2020","journal-title":"Life Sci. Alliance"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.coviro.2014.06.002","article-title":"Antiviral drugs specific for coronaviruses in preclinical development","volume":"8","author":"Adedeji","year":"2014","journal-title":"Curr. Opin. Virol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"100011","DOI":"10.1016\/j.chphi.2021.100011","article-title":"Drug targets, mechanisms of drug action, and therapeutics against SARS-CoV-2","volume":"2","author":"Jena","year":"2021","journal-title":"Chem. Phys. Impact"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1038\/s41422-020-0356-z","article-title":"Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease","volume":"30","author":"Ma","year":"2020","journal-title":"Cell Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"27381","DOI":"10.1073\/pnas.2010470117","article-title":"Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs","volume":"117","author":"Li","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Wang, K.Y., Liu, F., Jiang, R., Yang, X., You, T., Liu, X., Xiao, C.Q., Shi, Z., Jiang, H., and Rao, Z. (2020). Structure of Mpro from COVID-19 virus and discovery of its inhibitors. Nature, 289\u2013293.","DOI":"10.1038\/s41586-020-2223-y"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Kumar, V., Dhanjal, J.K., Bhargava, P., Kaul, A., Wang, J., Zhang, H., Kaul, S.C., Wadhwa, R., and Sundar, D. (2020). Withanone and Withaferin-A are predicted to interact with transmembrane protease serine 2 (TMPRSS2) and block entry of SARS-CoV-2 into cells. J. Biomol. Struct. Dyn., 1\u201313.","DOI":"10.1080\/07391102.2020.1775704"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1126\/science.abb4489","article-title":"Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease","volume":"368","author":"Dai","year":"2020","journal-title":"Science"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.2174\/1566524013666131111130058","article-title":"Biomedical applications of zinc oxide nanomaterials","volume":"13","author":"Zhang","year":"2013","journal-title":"Curr. Mol. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.msec.2017.08.058","article-title":"Enhancing the anti-gastric cancer activity of curcumin with biocompatible and pH sensitive PMMA-AA\/ZnO nanoparticles","volume":"82","author":"Dhivya","year":"2018","journal-title":"Mater. Sci. Eng."},{"key":"ref_51","first-page":"388","article-title":"Utilizing of (zinc oxide nano-spray) for disinfection against \u201cSARS-CoV-2\u201d and testing its biological effectiveness on some biochemical parameters during (COVID-19 pandemic)\u2014\u201cZnO nanoparticles have antiviral activity against (SARS-CoV-2)\u201d","volume":"11","author":"Alsawat","year":"2021","journal-title":"Mater. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2675","DOI":"10.2217\/nnm-2018-0089","article-title":"Polyethylene glycol-coated zinc oxide nanoparticle: An efficient nanoweapon to fight against herpes simplex virus type 1","volume":"13","author":"Tavakoli","year":"2018","journal-title":"Nanomedicine"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s11671-015-1158-y","article-title":"Serum proteins enhance dispersion stability and influence the cytotoxicity and dosimetry of ZnO nanoparticles in suspension and adherent cancer cell models","volume":"10","author":"Anders","year":"2015","journal-title":"Nanoscale Res. Lett."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"6506","DOI":"10.1021\/jp0570317","article-title":"Binding studies of molecular linkers to ZnO and MgZnO nanotip films","volume":"110","author":"Taratula","year":"2006","journal-title":"J. Phys. Chem. B"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.jphotobiol.2012.08.008","article-title":"Synthesis and characterization of doxorubicin modified ZnO\/PEG nanomaterials and its photodynamic action","volume":"116","author":"Hariharan","year":"2012","journal-title":"J. Photochem. Photobiol. B Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12929-019-0563-4","article-title":"Inhibition of H1N1 influenza virus infection by zinc oxide nanoparticles: Another emerging application of nanomedicine","volume":"26","author":"Ghaffari","year":"2019","journal-title":"J. Biomed. Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12645-017-0026-0","article-title":"Biological mechanisms of gold nanoparticle radiosensitization","volume":"8","author":"Rosa","year":"2017","journal-title":"Cancer Nanotechnol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s11671-018-2532-3","article-title":"Properties of zinc oxide nanoparticles and their activity against microbes","volume":"13","author":"Siddiqi","year":"2018","journal-title":"Nanoscale Res. Lett."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s10822-013-9644-8","article-title":"Protein and ligand preparation: Parameters, protocols, and influence on virtual screening enrichments","volume":"27","author":"Sastry","year":"2013","journal-title":"J. Comput. Mol. Des."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1021\/acs.jctc.5b00864","article-title":"OPLS3: A force field providing broad coverage of drug-like small molecules and proteins","volume":"12","author":"Harder","year":"2016","journal-title":"J. Chem. Theory Comput."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3004","DOI":"10.1021\/acs.jmedchem.9b01689","article-title":"Novel, self-assembling dimeric inhibitors of human \u03b2 tryptase","volume":"63","author":"Giardina","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_62","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. Mol. Des."},{"key":"ref_63","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. Mol. Des."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"357","DOI":"10.3389\/fnmol.2017.00357","article-title":"Combinatorial in silico strategy towards identifying potential hotspots during inhibition of structurally identical HDAC1 and HDAC2 enzymes for effective chemotherapy against neurological disorders","volume":"10","author":"Ganai","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"ref_65","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_66","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_67","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-ligand complexes","volume":"49","author":"Friesner","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1002\/prot.10613","article-title":"A hierarchical approach to all-atom protein loop prediction","volume":"55","author":"Jacobson","year":"2004","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_69","unstructured":"Chow, E., Rendleman, C.A., Bowers, K.J., Dror, R.O., Hughes, D.H., Gullingsrud, J., Sacerdoti, F.D., and Shaw, D.E. (2008). Desmond Performance on a Cluster of Multicore Processors, D. E. Shaw Research Technical Report DESRES\/TR--2008-01, D. E. Shaw."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1002\/prot.24209","article-title":"Starting-structure dependence of nanosecond timescale intersubstate transitions and reproducibility of MD-derived order parameters","volume":"81","author":"Zeiske","year":"2013","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1002\/prot.24276","article-title":"Contributions of water transfer energy to protein-ligand association and dissociation barriers: Watermap analysis of a series of p38\u03b1 MAP kinase inhibitors","volume":"81","author":"Pearlstein","year":"2013","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2586","DOI":"10.2174\/1568026617666170414141452","article-title":"Calculating water thermodynamics in the binding site of proteins\u2014Applications of WaterMap to drug discovery","volume":"17","author":"Cappel","year":"2017","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2817","DOI":"10.1021\/ja0771033","article-title":"Role of the active-site solvent in the thermodynamics of factor Xa ligand binding","volume":"130","author":"Abel","year":"2008","journal-title":"J. Am. Chem. Soc."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1073\/pnas.0610202104","article-title":"Motifs for molecular recognition exploiting hydrophobic enclosure in protein-ligand binding","volume":"104","author":"Young","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1021\/jm500373x","article-title":"Optimization of potent DFG-in inhibitors of platelet derived growth factor receptor\u03b2 (PDGF-R\u03b2) guided by water thermodynamics","volume":"58","author":"Horbert","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"3531","DOI":"10.1021\/jp9723574","article-title":"Inhomogeneous fluid approach to solvation thermodynamics. 1. Theory","volume":"102","author":"Lazaridis","year":"1998","journal-title":"J. Phys. Chem. B"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3542","DOI":"10.1021\/jp972358w","article-title":"Inhomogeneous fluid approach to solvation thermodynamics. 2. Applications to simple fluids","volume":"102","author":"Lazaridis","year":"1998","journal-title":"J. Phys. Chem. B"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3782","DOI":"10.1021\/acs.jcim.9b00367","article-title":"Reaction-based enumeration, active learning, and free energy calculations to rapidly explore synthetically tractable chemical space and optimize potency of cyclin-dependent kinase 2 inhibitors","volume":"59","author":"Konze","year":"2019","journal-title":"J. Chem. Inf. Model."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Mostafa, A., Kandeil, A., Elshaier, Y.A.M.M., Kutkat, O., Moatasim, Y., Rashad, A.A., Shehata, M., Gomaa, M.R., Mahrous, N., and Mahmoud, S.H. (2020). FDA-approved drugs with potent in vitro antiviral activity against severe acute respiratory syndrome coronavirus 2. Pharmaceuticals, 13.","DOI":"10.3390\/ph13120443"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Soliman, S.S.M., Alhamidi, T.B., Abdin, S., Almehdi, A.M., Semreen, M.H., Alhumaidi, R.B., Shakartalla, S.B., Haider, M., Husseiny, M.I., and Omar, H.A. (2020). Effective targeting of breast cancer cells (MCF7) via novel biogenic synthesis of gold nanoparticles using cancer-derived metabolites. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0240156"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"109318","DOI":"10.1016\/j.cbi.2020.109318","article-title":"Critical discovery and synthesis of novel antibacterial and resistance-modifying agents inspired by plant phytochemical defense mechanisms","volume":"333","author":"Soliman","year":"2020","journal-title":"Chem. Biol. Interact."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"4417","DOI":"10.1038\/s41467-020-18233-x","article-title":"Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease","volume":"11","author":"Fu","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"12725","DOI":"10.1021\/acs.jmedchem.0c01063","article-title":"Discovery of ketone-based covalent inhibitors of coronavirus 3CL proteases for the potential therapeutic treatment of COVID-19","volume":"63","author":"Hoffman","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"39971","DOI":"10.1021\/acsami.7b11219","article-title":"Exploration of zinc oxide nanoparticles as a multitarget and multifunctional anticancer nanomedicine","volume":"9","author":"Wang","year":"2017","journal-title":"ACS Appl. Mater. Interfaces"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/9057\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:49:23Z","timestamp":1760165363000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/9057"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,22]]},"references-count":85,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ijms22169057"],"URL":"https:\/\/doi.org\/10.3390\/ijms22169057","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,22]]}}}