{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T21:06:57Z","timestamp":1780088817532,"version":"3.54.0"},"reference-count":35,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T00:00:00Z","timestamp":1615420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004919","name":"King Abdulaziz City for Science and Technology","doi-asserted-by":"publisher","award":["5-20-01-021-0005"],"award-info":[{"award-number":["5-20-01-021-0005"]}],"id":[{"id":"10.13039\/501100004919","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Considering the urgency of the COVID-19 pandemic, we developed a receptor-based pharmacophore model for identifying FDA-approved drugs and hits from natural products. The COVID-19 main protease (Mpro) was selected for the development of the pharmacophore model. The model consisted of a hydrogen bond acceptor, donor, and hydrophobic features. These features demonstrated good corroboration with a previously reported model that was used to validate the present model, showing an RMSD value of 0.32. The virtual screening was carried out using the ZINC database. A set of 208,000 hits was extracted and filtered using the ligand pharmacophore mapping, applying the lead-like properties. Lipinski\u2019s filter and the fit value filter were used to minimize hits to the top 2000. Simultaneous docking was carried out for 200 hits for natural drugs belonging to the FDA-approved drug database. The top 28 hits from these experiments, with promising predicted pharmacodynamic and pharmacokinetic properties, are reported here. To optimize these hits as Mpro inhibitors and potential treatment options for COVID-19, bench work investigations are needed.<\/jats:p>","DOI":"10.3390\/molecules26061549","type":"journal-article","created":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T20:17:40Z","timestamp":1615493860000},"page":"1549","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Receptor-Based Pharmacophore Modeling in the Search for Natural Products for COVID-19 Mpro"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3443-386X","authenticated-orcid":false,"given":"Mohd","family":"Saeed","sequence":"first","affiliation":[{"name":"Department of Biology, College of Sciences, University of Ha\u2019il, Hail 2440, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"Saeed","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, University of Ha\u2019il, Hail 2440, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0144-6517","authenticated-orcid":false,"given":"Md Jahoor","family":"Alam","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Sciences, University of Ha\u2019il, Hail 2440, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mousa","family":"Alreshidi","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Sciences, University of Ha\u2019il, Hail 2440, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12035-020-02022-0","article-title":"Current status of multiple drug molecules, and vaccines: An update in SARS-CoV-2 therapeutics","volume":"57","author":"Kandimalla","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.7150\/ijbs.45134","article-title":"COVID-19: What has been learned and to be learned about the novel coronavirus disease","volume":"16","author":"Yi","year":"2020","journal-title":"Int. J. Biol. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1016\/S2213-2600(20)30418-5","article-title":"Human recombinant soluble ACE2 in severe COVID-19","volume":"8","author":"Zoufaly","year":"2020","journal-title":"Lancet Respir. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"12359","DOI":"10.1021\/acs.jmedchem.0c00606","article-title":"COVID-19: Drug targets and potential treatments","volume":"63","author":"Gil","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"56","DOI":"10.4103\/ijp.IJP_115_20","article-title":"Drug targets for corona virus: A systematic review","volume":"52","author":"Prajapat","year":"2020","journal-title":"Indian J. Pharmacol."},{"key":"ref_6","first-page":"1","article-title":"Human recombinant soluble ACE2 (hrsACE2) shows promise for treating severe COVID19","volume":"5","author":"Stockand","year":"2020","journal-title":"Signal. Transduct. Target. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/s41579-020-00468-6","article-title":"Coronavirus biology and replication: Implications for SARS-CoV-2","volume":"19","author":"Kratzel","year":"2021","journal-title":"Nat. Rev. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12038-020-00067-w","article-title":"Drug targets for COVID-19 therapeutics: Ongoing global efforts","volume":"45","author":"Saxena","year":"2020","journal-title":"J. Biosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"40264","DOI":"10.1039\/D0RA06038K","article-title":"Pharmacophore-based approaches in the rational repurposing technique for FDA approved drugs targeting SARS-CoV-2 Mpro","volume":"10","author":"Balaramnavar","year":"2020","journal-title":"RSC Adv."},{"key":"ref_10","first-page":"1","article-title":"SARS-CoV-2 M pro inhibitors and activity-based probes for patient-sample imaging","volume":"17","author":"Rut","year":"2020","journal-title":"Nat. Chem. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Saeed, M., Saeed, A., Alam, M.J., and Alreshidi, M. (2020). Identification of Persuasive Antiviral Natural Compounds for COVID-19 by Targeting Endoribonuclease NSP15: A Structural-Bioinformatics Approach. Molecules, 25.","DOI":"10.3390\/molecules25235657"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1016\/j.drudis.2010.03.013","article-title":"Pharmacophore modeling and applications in drug discovery: Challenges and recent advances","volume":"15","author":"Yang","year":"2010","journal-title":"Drug Discov. Today"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.2174\/1568026611313090006","article-title":"Methods and applications of structure based pharmacophores in drug discovery","volume":"13","author":"Pirhadi","year":"2013","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1007\/BF00126217","article-title":"LUDI: Rule-based automatic design of new substituents for enzyme inhibitor leads","volume":"6","year":"1992","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1021\/ci800064z","article-title":"Hot-spots-guided receptor-based pharmacophores (HS-Pharm): A knowledge-based approach to identify ligand-anchoring atoms in protein cavities and prioritize structure-based pharmacophores","volume":"48","author":"Barillari","year":"2008","journal-title":"J. Chem. Inf. Model."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.bcab.2018.12.014","article-title":"Conceptual design of hybrid PCSK9 lead inhibitors against coronary artery disease","volume":"17","author":"Puratchikody","year":"2019","journal-title":"Biocatal. Agric. Biotechnol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/s12539-013-0157-x","article-title":"High throughput virtual screening and E-pharmacophore filtering in the discovery of new BACE-1 inhibitors","volume":"5","author":"Muthusamy","year":"2013","journal-title":"Interdiscip. Sci. Comput. Life Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3315","DOI":"10.1021\/jm051197e","article-title":"MolDock: A new technique for high-accuracy molecular docking","volume":"49","author":"Thomsen","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_19","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_20","doi-asserted-by":"crossref","unstructured":"Chandra, A., Chaudhary, M., Qamar, I., Singh, N., and Nain, V. (2021). In silico identification and validation of natural antiviral compounds as potential inhibitors of SARS-CoV-2 methyltransferase. J. Biomol. Struct. Dyn., 1\u201311.","DOI":"10.1080\/07391102.2021.1886174"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"56","DOI":"10.3390\/metabo5010056","article-title":"The role of colonic bacteria in the metabolism of the natural isoflavone daidzin to equol","volume":"5","author":"Rafii","year":"2015","journal-title":"Metabolites"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Elfiky, A.A. (2020). SARS-CoV-2 RNA dependent RNA polymerase (RdRp) targeting: An in silico perspective. J. Biomol. Struct. Dyn., 1\u20139.","DOI":"10.1080\/07391102.2020.1761882"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.ijantimicag.2019.03.017","article-title":"Phloretin inhibits Zika virus infection by interfering with cellular glucose utilisation","volume":"54","author":"Lin","year":"2019","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1007\/s11101-017-9500-x","article-title":"Health effects of phloretin: From chemistry to medicine","volume":"16","author":"Behzad","year":"2017","journal-title":"Phytochem. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1016\/j.bcp.2006.12.018","article-title":"Rosmarinic acid inhibits indoleamine 2, 3-dioxygenase expression in murine dendritic cells","volume":"73","author":"Lee","year":"2007","journal-title":"Biochem. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"571459","DOI":"10.3389\/fphar.2020.571459","article-title":"Pharmacological activities of Psoralidin: A comprehensive review of the molecular mechanisms of action","volume":"11","author":"Kamiloglu","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.2174\/1871527313666141023120843","article-title":"Identification of potent caspase-3 inhibitors for treatment of multi-neurodegenerative diseases using pharmacophore modeling and docking approaches","volume":"13","author":"Ahmad","year":"2014","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/BF02174464","article-title":"Automated chemical hypothesis generation and database searching with Catalyst\u00ae","volume":"3","author":"Sprague","year":"1995","journal-title":"Perspect. Drug Discov. Des."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/s41586-020-2223-y","article-title":"Structure of M pro from SARS-CoV-2 and discovery of its inhibitors","volume":"582","author":"Jin","year":"2020","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/BF00124387","article-title":"The computer program LUDI: A new method for the de novo design of enzyme inhibitors","volume":"6","year":"1992","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1002\/jcc.21367","article-title":"CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields","volume":"31","author":"Vanommeslaeghe","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1021\/ci00021a032","article-title":"National Cancer Institute drug information system 3D database","volume":"34","author":"Milne","year":"1994","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1021\/ci049714+","article-title":"ZINC--a free database of commercially available compounds for virtual screening","volume":"45","author":"Irwin","year":"2005","journal-title":"J. Chem. Inf. Model."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Gehlhaar, D.K., Bouzida, D., and Rejto, P.A. (1998, January 25\u201327). Fully automated and rapid flexible docking of inhibitors covalently bound to serine proteases. Proceedings of the International Conference on Evolutionary Programming, San Diego, CA, USA.","DOI":"10.1007\/BFb0040797"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6036","DOI":"10.1016\/j.bmc.2015.06.039","article-title":"Targeting zoonotic viruses: Structure-based inhibition of the 3C-like protease from bat coronavirus HKU4\u2014The likely reservoir host to the human coronavirus that causes Middle East Respiratory Syndrome (MERS)","volume":"23","author":"John","year":"2015","journal-title":"Bioorg. Med. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/6\/1549\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:34:22Z","timestamp":1760160862000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/6\/1549"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,11]]},"references-count":35,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["molecules26061549"],"URL":"https:\/\/doi.org\/10.3390\/molecules26061549","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,11]]}}}