{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T18:21:14Z","timestamp":1774290074519,"version":"3.50.1"},"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004919","name":"King Abdulaziz City for Science and Technology","doi-asserted-by":"publisher","award":["5-21-01-001-0003"],"award-info":[{"award-number":["5-21-01-001-0003"]}],"id":[{"id":"10.13039\/501100004919","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Neuropilin-1 (NRP-1) functions as an essential co-receptor for SARS-CoV-2, facilitating viral entry by binding the spike protein\u2019s C-end rule (CendR) motif in its b1 domain, yet it has received less attention than ACE2 in therapeutic development. This\n                    <jats:italic>in silico<\/jats:italic>\n                    study evaluates plant-derived polyphenols as potential selective inhibitors of the NRP-1 CendR pocket to disrupt SARS-CoV-2 engagement, addressing limitations of synthetic inhibitors like EG01377, which exhibit modest affinity (\u22125.83 kcal\/mol) and potential off-target risks. High-throughput molecular docking of 10,000 phytochemicals using AutoDock Vina identified 10 polyphenols with binding affinities ranging from \u22129.87 to \u22126.63 kcal\/mol, led by 6\u201c-O-acetyldaidzin (-9.87 kcal\/mol) and phloretin (-8.64 kcal\/mol), forming stable hydrogen bonds and \u03c0-cation interactions with critical residues (e.g., THR-401, GLU-367 for 6\u201d-O-acetyldaidzin; PRO-311, ILE-400 for phloretin), as visualized in Discovery Studio. Notably, four of the top inhibitors are isoflavonoid derivatives, highlighting a chemical class enrichment. Molecular dynamics simulations over 100 ns using Desmond indicated moderate complex stability (RMSD: 0.6\u20133.8 \u00c5; RMSF &lt;0.5 \u00c5 at binding site\n                    <jats:bold>).<\/jats:bold>\n                    ADMET-Tox profiling via SwissADME and ProTox-II revealed drug-like properties, including high gastrointestinal absorption (&gt;70% for leads) and low toxicity (classes 4\u20135), though 6\u201d-O-acetyldaidzin shows limited bioavailability due to its high H-bond acceptor count (10) and large size, suggesting need for formulation optimization. The NRP-1 b1 homology model, built with SWISS-MODEL, exhibited high fidelity (GMQE: 0.79; Ramachandran favored regions: 90.3%\n                    <jats:bold>).<\/jats:bold>\n                    This focused computational screening of polyphenols against NRP-1 complements prior studies and identifies candidates for experimental validation as potential SARS-CoV-2 inhibitors. Limitations include the\n                    <jats:italic>in silico<\/jats:italic>\n                    nature, and lack of membrane\/sialic acid models, necessitating\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    testing against SARS-CoV-2 variants.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0345051","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T17:23:26Z","timestamp":1774286606000},"page":"e0345051","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of polyphenols as novel neuropilin-1 cendR pocket inhibitors to block SARS-CoV-2 entry and enhance variant resistance"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7036-3888","authenticated-orcid":true,"given":"Farid","family":"Ataya","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abir","family":"Alamro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amani","family":"Alghamdi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dalia","family":"Fouad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"key":"pone.0345051.ref001","article-title":"COVID-19 epidemiological update \u2013 September 2025","author":"World Health Organization","year":"2025","journal-title":"WHO"},{"issue":"6483","key":"pone.0345051.ref002","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1126\/science.abb2507","article-title":"Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation","volume":"367","author":"D Wrapp","year":"2020","journal-title":"Science"},{"issue":"5","key":"pone.0345051.ref003","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s00335-021-09880-6","article-title":"SNPs at 3\u2019UTR of APOL1 and miR-6741-3p target sites associated with kidney diseases more susceptible to SARS-COV-2 infection: in silco and in vitro studies","volume":"32","author":"M Safdar","year":"2021","journal-title":"Mamm Genome"},{"issue":"6518","key":"pone.0345051.ref004","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1126\/science.abd3072","article-title":"Neuropilin-1 is a host factor for SARS-CoV-2 infection","volume":"370","author":"JL Daly","year":"2020","journal-title":"Science"},{"issue":"6518","key":"pone.0345051.ref005","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1126\/science.abd2985","article-title":"Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity","volume":"370","author":"L Cantuti-Castelvetri","year":"2020","journal-title":"Science"},{"issue":"1","key":"pone.0345051.ref006","first-page":"312","article-title":"ACE2 Expression Patterns Across Mammals and Key Findings for SARS-CoV-2 Model Development for Human and Animal Research","volume":"45","author":"A Ali","year":"2025","journal-title":"Pak Vet J"},{"issue":"1","key":"pone.0345051.ref007","article-title":"In-silico natural product database mining for novel neuropilin-1 inhibitors: molecular docking, molecular dynamics and binding energy computations","volume":"17","author":"MAA Ibrahim","year":"2023","journal-title":"Journal of Taibah University for Science"},{"key":"pone.0345051.ref008","first-page":"143","article-title":"Neuropilin 1: A Novel Entry Factor for SARS-CoV-2 Infection and a Potential Therapeutic Target","volume":"15","author":"E Chekol Abebe","year":"2021","journal-title":"Biologics"},{"issue":"2","key":"pone.0345051.ref009","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1016\/j.drudis.2018.10.004","article-title":"Targeting VEGF-neuropilin interactions: a promising antitumor strategy","volume":"24","author":"K Peng","year":"2019","journal-title":"Drug Discov Today"},{"issue":"14","key":"pone.0345051.ref010","doi-asserted-by":"crossref","first-page":"2325","DOI":"10.3390\/nu17142325","article-title":"Polyphenols as antiviral agents: their potential against a range of virus types","volume":"17","author":"N Co\u015fkun","year":"2025","journal-title":"Nutrients"},{"issue":"3","key":"pone.0345051.ref011","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1002\/ptr.8123","article-title":"Flavonoids derived from medicinal plants as a COVID-19 treatment","volume":"38","author":"M Sopjani","year":"2024","journal-title":"Phytother Res"},{"key":"pone.0345051.ref012","doi-asserted-by":"crossref","first-page":"105224","DOI":"10.1016\/j.phrs.2020.105224","article-title":"Natural product derived phytochemicals in managing acute lung injury by multiple mechanisms","volume":"163","author":"Y-Q He","year":"2021","journal-title":"Pharmacol Res"},{"issue":"4","key":"pone.0345051.ref013","doi-asserted-by":"crossref","first-page":"558","DOI":"10.3390\/futurepharmacol2040034","article-title":"Computational Screening of Plant-Derived Natural Products against SARS-CoV-2 Variants","volume":"2","author":"WA Ansari","year":"2022","journal-title":"Future Pharmacology"},{"issue":"1","key":"pone.0345051.ref014","doi-asserted-by":"crossref","first-page":"24","DOI":"10.4103\/2225-4110.124335","article-title":"Antiviral natural products and herbal medicines","volume":"4","author":"L-T Lin","year":"2014","journal-title":"J Tradit Complement Med"},{"issue":"1","key":"pone.0345051.ref015","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s13099-023-00535-2","article-title":"In-silico computational approaches to study microbiota impacts on diseases and pharmacotherapy","volume":"15","author":"H Shokri Garjan","year":"2023","journal-title":"Gut Pathog"},{"issue":"2","key":"pone.0345051.ref016","first-page":"605","article-title":"Dose-dependent effects and safety assessment of inactivated covid-19 vaccine: a comprehensive preclinical study","volume":"45","author":"K Sonmez","year":"2025","journal-title":"Pak Vet J"},{"key":"pone.0345051.ref017","doi-asserted-by":"crossref","DOI":"10.1093\/jas\/skae248","article-title":"In silico analysis of polyphenols modulate bovine PPAR\u03b3 to increase milk fat synthesis in dairy cattle via the MAPK signaling pathways","volume":"102","author":"M Safdar","year":"2024","journal-title":"J Anim Sci"},{"key":"pone.0345051.ref018","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":"A Daina","year":"2017","journal-title":"Sci Rep"},{"key":"pone.0345051.ref019","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkl842","article-title":"NCBI reference sequences (RefSeq): a curated non-redundant sequence database of genomes, transcripts and proteins","volume":"35","author":"KD Pruitt","year":"2007","journal-title":"Nucleic Acids Res"},{"key":"pone.0345051.ref020","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gky427","article-title":"SWISS-MODEL: homology modelling of protein structures and complexes","volume":"46","author":"A Waterhouse","year":"2018","journal-title":"Nucleic Acids Res"},{"issue":"6","key":"pone.0345051.ref021","doi-asserted-by":"crossref","first-page":"1765","DOI":"10.1093\/bioinformatics\/btz828","article-title":"QMEANDisCo-distance constraints applied on model quality estimation","volume":"36","author":"G Studer","year":"2020","journal-title":"Bioinformatics"},{"key":"pone.0345051.ref022","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1385\/1-59259-890-0:571","article-title":"Protein Identification and Analysis Tools on the ExPASy Server","author":"E Gasteiger","year":"2005","journal-title":"The Proteomics Protocols Handbook. Humana Press"},{"key":"pone.0345051.ref023","article-title":"PubChem in 2021: new data content and improved web interfaces","volume":"49","author":"S Kim","year":"2021","journal-title":"Nucleic Acids Res"},{"key":"pone.0345051.ref024","doi-asserted-by":"crossref","DOI":"10.1093\/database\/bat070","article-title":"Phenol-Explorer 3.0: a major update of the Phenol-Explorer database to incorporate data on the effects of food processing on polyphenol content","volume":"2013","author":"JA Rothwell","year":"2013","journal-title":"Database (Oxford)"},{"issue":"11","key":"pone.0345051.ref025","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.1021\/acs.jcim.5b00559","article-title":"ZINC 15--Ligand Discovery for Everyone","volume":"55","author":"T Sterling","year":"2015","journal-title":"J Chem Inf Model"},{"key":"pone.0345051.ref026","volume-title":"Discovery Studio modeling environment, release 2021","author":"BIOVIA","year":"2021"},{"key":"pone.0345051.ref027","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":"NM O\u2019Boyle","year":"2011","journal-title":"J Cheminform"},{"key":"pone.0345051.ref028","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/978-1-4939-2269-7_19","article-title":"Small-molecule library screening by docking with PyRx","volume":"1263","author":"S Dallakyan","year":"2015","journal-title":"Methods Mol Biol"},{"issue":"16","key":"pone.0345051.ref029","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":"GM Morris","year":"2009","journal-title":"J Comput Chem"},{"issue":"2","key":"pone.0345051.ref030","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":"31","author":"O Trott","year":"2010","journal-title":"J Comput Chem"},{"key":"pone.0345051.ref031","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gky318","article-title":"ProTox-II: a webserver for the prediction of toxicity of chemicals","volume":"46","author":"P Banerjee","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"pone.0345051.ref032","volume-title":"Desmond molecular dynamics system, release 2021-4","author":"L Schr\u00f6dinger","year":"2021"},{"issue":"2","key":"pone.0345051.ref033","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of simple potential functions for simulating liquid water","volume":"79","author":"WL Jorgensen","year":"1983","journal-title":"J Chem Phys"},{"issue":"5","key":"pone.0345051.ref034","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1021\/ct900587b","article-title":"Prediction of Absolute Solvation Free Energies using Molecular Dynamics Free Energy Perturbation and the OPLS Force Field","volume":"6","author":"D Shivakumar","year":"2010","journal-title":"J Chem Theory Comput"},{"issue":"4","key":"pone.0345051.ref035","first-page":"1201","article-title":"Evaluating the cardioprotective efficacy of diosmin against LPS-induced cardiac dysfunction: in silico docking and experimental investigations","volume":"44","author":"B Yan","year":"2024","journal-title":"Pak Vet J"},{"issue":"3","key":"pone.0345051.ref036","doi-asserted-by":"crossref","DOI":"10.1111\/rda.70033","article-title":"Phytoestrogens Modulate Bovine G Protein\u2010Coupled Receptors and Play a Critical Role in Regulating Reproductive Functions in Animals","volume":"60","author":"M Safdar","year":"2025","journal-title":"Reproduction in Domestic Animals"},{"issue":"4","key":"pone.0345051.ref037","doi-asserted-by":"crossref","first-page":"442","DOI":"10.3906\/biy-2012-52","article-title":"In silico drug repositioning against human NRP1 to block SARS-CoV-2 host entry","volume":"45","author":"\u015e G\u00fcl","year":"2021","journal-title":"Turk J Biol"},{"issue":"9","key":"pone.0345051.ref038","doi-asserted-by":"crossref","first-page":"4135","DOI":"10.1021\/acs.jmedchem.8b00210","article-title":"Small Molecule Neuropilin-1 Antagonists Combine Antiangiogenic and Antitumor Activity with Immune Modulation through Reduction of Transforming Growth Factor Beta (TGF\u03b2) Production in Regulatory T-Cells","volume":"61","author":"J Powell","year":"2018","journal-title":"J Med Chem"},{"issue":"22","key":"pone.0345051.ref039","doi-asserted-by":"crossref","first-page":"12164","DOI":"10.1080\/07391102.2023.2268185","article-title":"Identification of phytochemicals as putative ligands for the targeted modulation of peroxisome proliferator-activated receptor \u03b1 (PPAR\u03b1) in animals","volume":"42","author":"F-U Hassan","year":"2024","journal-title":"J Biomol Struct Dyn"},{"issue":"3","key":"pone.0345051.ref040","first-page":"592","article-title":"A review on the use of phytochemicals for the control of zoonotic Giardiasis","volume":"44","author":"BS Alawfi","year":"2024","journal-title":"Pak Vet J"},{"issue":"1","key":"pone.0345051.ref041","first-page":"55","article-title":"Efficacy and comparative toxicity of phytochemical compounds extracted from aromatic perennial trees and herbs against vector borne Culex pipiens (Diptera: Culicidae) and Hyalomma dromedarii (Acari: Ixodidae) as green insecticides","volume":"44","author":"MM Baz","year":"2024","journal-title":"Pak Vet J"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0345051","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T17:23:34Z","timestamp":1774286614000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0345051"}},"subtitle":[],"editor":[{"given":"Yusuf Oloruntoyin","family":"Ayipo","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2026,3,23]]},"references-count":41,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3,23]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0345051","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,23]]}}}