{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T04:48:40Z","timestamp":1789534120445,"version":"build-2803163510"},"reference-count":45,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T00:00:00Z","timestamp":1631664000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Taif University Researchers Supporting Project","award":["TURSP-2020\/51"],"award-info":[{"award-number":["TURSP-2020\/51"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>SARS-CoV-2 virus mutations might increase its virulence, and thus the severity and duration of the ongoing pandemic. Global drug discovery campaigns have successfully developed several vaccines to reduce the number of infections by the virus. However, finding a small molecule pharmaceutical that is effective in inhibiting SARS-CoV-2 remains a challenge. Natural products are the origin of many currently used pharmaceuticals and, for this reason, a library of in-house fungal extracts were screened to assess their potential to inhibit the main viral protease Mpro in vitro. The extract of Penicillium citrinum, TDPEF34, showed potential inhibition and was further analysed to identify potential Mpro inhibitors. Following bio-guided isolation, a series of benzodiazepine alkaloids cyclopenins with good-to-moderate activity against SARS-CoV-2 Mpro were identified. The mode of enzyme inhibition of these compounds was predicted by docking and molecular dynamic simulation. Compounds 1 (isolated as two conformers of S- and R-isomers), 2, and 4 were found to have promising in vitro inhibitory activity towards Mpro, with an IC50 values range of 0.36\u20130.89 \u00b5M comparable to the positive control GC376. The in silico investigation revealed compounds to achieve stable binding with the enzyme active site through multiple H-bonding and hydrophobic interactions. Additionally, the isolated compounds showed very good drug-likeness and ADMET properties. Our findings could be utilized in further in vitro and in vivo investigations to produce anti-SARS-CoV-2 drug candidates. These findings also provide critical structural information that could be used in the future for designing potent Mpro inhibitors.<\/jats:p>","DOI":"10.3390\/biom11091366","type":"journal-article","created":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T12:00:44Z","timestamp":1631707244000},"page":"1366","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Bioguided Isolation of Cyclopenin Analogues as Potential SARS-CoV-2 Mpro Inhibitors from Penicillium citrinum TDPEF34"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0998-4187","authenticated-orcid":false,"given":"Bathini","family":"Thissera","sequence":"first","affiliation":[{"name":"School of Computing, Engineering & Physical Science, University of the West of Scotland, Paisley PA1 2BE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1442-183X","authenticated-orcid":false,"given":"Ahmed M.","family":"Sayed","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy, Nahda University, Beni-Suef 62513, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0952-5984","authenticated-orcid":false,"given":"Marwa H. A.","family":"Hassan","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9636-7485","authenticated-orcid":false,"given":"Sayed F.","family":"Abdelwahab","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Industrial Pharmacy, Taif College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ngozi","family":"Amaeze","sequence":"additional","affiliation":[{"name":"School of Health and Life Sciences, University of the West of Scotland, Paisley PA1 2BE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9559-0821","authenticated-orcid":false,"given":"Valeria T.","family":"Semler","sequence":"additional","affiliation":[{"name":"School of Computing, Engineering & Physical Science, University of the West of Scotland, Paisley PA1 2BE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faizah N.","family":"Alenezi","sequence":"additional","affiliation":[{"name":"The Public Authority for Applied Education and Training, Adailiyah 00965, Kuwait"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2460-1893","authenticated-orcid":false,"given":"Mohammed","family":"Yaseen","sequence":"additional","affiliation":[{"name":"School of Computing, Engineering & Physical Science, University of the West of Scotland, Paisley PA1 2BE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4822-1895","authenticated-orcid":false,"given":"Hani A.","family":"Alhadrami","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, P.O. Box 80402, Jeddah 21589, Saudi Arabia"},{"name":"Molecular Diagnostic Lab, King Abdulaziz University Hospital, King Abdulaziz University, P.O. Box 80402, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7040-4500","authenticated-orcid":false,"given":"Lassaad","family":"Belbahri","sequence":"additional","affiliation":[{"name":"Laboratory of Soil Biology, University of Neuchatel, 2000 Neuchatel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4043-2687","authenticated-orcid":false,"given":"Mostafa E.","family":"Rateb","sequence":"additional","affiliation":[{"name":"School of Computing, Engineering & Physical Science, University of the West of Scotland, Paisley PA1 2BE, UK"},{"name":"Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Meston Walk, Aberdeen AB24 3UE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1021\/acs.jnatprod.0c01324","article-title":"Anti-SARS-CoV-2 activity of Andrographis paniculata extract and its major component andrographolide in human lung epithelial cells and cytotoxicity evaluation in major organ cell representatives","volume":"84","author":"Suksatu","year":"2021","journal-title":"J. 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