{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T12:15:46Z","timestamp":1788437746755,"version":"build-2803163510"},"reference-count":75,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002383","name":"King Saud University","doi-asserted-by":"publisher","award":["ORF-2026-583"],"award-info":[{"award-number":["ORF-2026-583"]}],"id":[{"id":"10.13039\/501100002383","id-type":"DOI","asserted-by":"publisher"}]},{"award":["ORF-2026-583"],"award-info":[{"award-number":["ORF-2026-583"]}],"id":[{"id":"https:\/\/ror.org\/02f81g417","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Curr. Issues Mol. Biol.","CIMB"],"abstract":"<jats:p>Emerging SARS-CoV-2 variants highlight the need for orally active, low-toxicity antivirals. We designed seven para-substituted flavonoid hybrids (M1\u2013M7) against the main protease (Mpro). In silico ADME filtering revealed zero Lipinski, Veber, or Ghose violations, a SwissADME bioavailability score of 0.55, and selected favorable predicted absorption and transporter endpoints relative to lopinavir, without implying measured pharmacokinetic superiority. ProTox-III indicated that amino and nitro substitution increased predicted genotoxicity liabilities, whereas cyano and methoxy substitution reduced selected endocrine-related signals. AutoDock Vina docking to Mpro (PDB 9C8Q; redocking RMSD 0.316 \u00c5) ranked the nitro analogue M6 first among the designed compounds (\u22128.1 kcal mol\u22121), with contacts involving His41 and neighboring active-site residues. During the 100 ns GROMACS simulations, the protein backbone remained stable, whereas M6 adopted a late reoriented pose that was retained in the active-site region and supported by late-window per-residue energetic contributions. DFT calculations at the B3LYP\/6-311G(d,p) level identified the narrowest HOMO-LUMO gap (3.44 eV) and highest electrophilicity (\u03c9 = 6.2 eV) for M6. Overall, M6 is prioritized as a computational lead requiring Mpro inhibition, antiviral, and cytotoxicity validation.<\/jats:p>","DOI":"10.3390\/cimb48090891","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T11:33:32Z","timestamp":1788262412000},"page":"891","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated Computational Study Prioritizes Drug-like Para-Flavonoids as Candidate SARS-CoV-2 Mpro Inhibitors"],"prefix":"10.3390","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3640-9612","authenticated-orcid":false,"given":"Jawaher H.","family":"Alqahtani","sequence":"first","affiliation":[{"name":"Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Mohammed","family":"Ouachekradi","sequence":"additional","affiliation":[{"name":"Laboratory of Applied Chemistry and Environment, Faculty of Science, Mohammed First University, BP 717, Oujda 60000, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8311-2513","authenticated-orcid":false,"given":"Bahia","family":"Abdelfattah","sequence":"additional","affiliation":[{"name":"Laboratory of Physical Chemistry of Materials, Natural Substances and Environment, Chemistry Department, Faculty of Sciences and Techniques of Tangier, Tangier 90090, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"}]},{"given":"Amal","family":"Elrherabi","sequence":"additional","affiliation":[{"name":"Laboratory for Research in Life and Drug Sciences (LRSVM), Pharmacology, Toxicology, and Applied Plant Sciences, Faculty of Medicine and Pharmacy, Mohammed First University, BP 717, Oujda 60000, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3013-1354","authenticated-orcid":false,"given":"Moneerah","family":"J. Alqahtani","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5658-9382","authenticated-orcid":false,"given":"Joe","family":"Miantezila Basilua","sequence":"additional","affiliation":[{"name":"BioSTM\u2014UR 7537 Biostatistics, Processing and Modelling of Biological Data, Paris Cit\u00e9 University, 75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9407-7576","authenticated-orcid":false,"given":"Oussama","family":"Khibech","sequence":"additional","affiliation":[{"name":"Laboratory of Applied Chemistry and Environment, Faculty of Science, Mohammed First University, BP 717, Oujda 60000, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Mohamed","family":"Bouhrim","sequence":"additional","affiliation":[{"name":"Biological Engineering Laboratory, Faculty of Sciences and Techniques, Sultan Moulay Slimane University, P.O. 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