{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T22:01:42Z","timestamp":1791237702743,"version":"4.1.0"},"reference-count":95,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T00:00:00Z","timestamp":1767830400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Aggregatibacter actinomycetemcomitans is a Gram-negative, facultative anaerobic, immobile oral bacterium responsible for the secretion of virulence factors, namely leukotoxin (LtxA), a large exotoxin of the RTX family that enables the bacterium to evade the immune system by destroying leukocytes, resulting in aggressive periodontitis (AP) leading to tooth loss. Methods: This study aimed to screen 106 molecules derived from Moroccan propolis in order to identify potential inhibitors of the active sites of LtxA based on molecular docking, ADMET property evaluation, and molecular dynamics (MD) simulation. Results: Epigallocatechin gallate (EGCg), used as a reference compound, showed binding energies of \u22126.9 kcal\/mol, \u22126.1 kcal\/mol, \u22126.5 kcal\/mol, and \u22125.9 kcal\/mol with the four active sites P1, P2, P3, and P4, respectively. By establishing conventional hydrogen bonds, pi-alkyl bonds, and non-covalent pi\u2013pi bonds. Chrysin and luteolin showed favorable binding affinities with the four active sites, named as follows: P1\u2013P4 (P1\u2013chrysin = \u22127.5 kcal\/mol; P2\u2013chrysin = \u22127.9 kcal\/mol; P3\u2013chrysin = \u22128.1 kcal\/mol; P4\u2013chrysin = \u22126.9 kcal\/mol; P1\u2013luteolin = \u22127.3 kcal\/mol; P2\u2013luteolin = \u22127.6 kcal\/mol; P3\u2013luteolin = \u22128.1 kcal\/mol; P4\u2013luteolin = \u22127.3 kcal\/mol). The binding affinity of these two propolis derivatives was stabilized by pi\u2212sigma bonds, pi\u2212alkyl bonds, conventional hydrogen bonds, pi-cation interactions, non-covalent pi\u2013pi bonds, and carbon\u2013hydrogen bonds. According to free energy calculations performed with Prime MM-GBSA, the complexes formed by chrysin demonstrated the most stable interactions due to Van der Waals and lipophilic forces. Luteolin formed significant interactions, but slightly weaker than those of chrysin. These results reveal the inhibitory potential of chrysin and luteolin with protein active sites. MD simulations corroborated the excellent stability of complexes formed by chrysin, as indicated by low RMSD values, suggesting favorable dynamic behavior. Conclusions: These results highlight the potential of chrysin as a versatile inhibitor capable of interacting with the four active sites. These findings are a strong foundation for further experimental confirmations.<\/jats:p>","DOI":"10.3390\/ph19010115","type":"journal-article","created":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T14:32:38Z","timestamp":1767882758000},"page":"115","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Chrysin and Luteolin from Moroccan Propolis to Prevent Aggressive Periodontitis Caused by Aggregatibacter actinomycetemcomitans Leukotoxin: A Computer-Aided Drug Design Approach"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-7929-9232","authenticated-orcid":false,"given":"Doha","family":"EL Meskini","sequence":"first","affiliation":[{"name":"Medical Biotechnology Laboratory (MedBiotech), Bioinova Research Center, Medical and Pharmacy School, Mohammed V University in Rabat, Rabat 10100, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fettouma","family":"Chraa","sequence":"additional","affiliation":[{"name":"Medical Biotechnology Laboratory (MedBiotech), Bioinova Research Center, Medical and Pharmacy School, Mohammed V University in Rabat, Rabat 10100, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihane","family":"Touhtouh","sequence":"additional","affiliation":[{"name":"Laboratory of Natural Resources and Environment, Polydisciplinary Faculty of Taza, Sidi Mohamed Ben Abdellah University of Fez, Taza 30050, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2306-9364","authenticated-orcid":false,"given":"Mouna","family":"Ouadghiri","sequence":"additional","affiliation":[{"name":"Medical Biotechnology Laboratory (MedBiotech), Bioinova Research Center, Medical and Pharmacy School, Mohammed V University in Rabat, Rabat 10100, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6281-426X","authenticated-orcid":false,"given":"Monica","family":"Gallo","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdelhakim","family":"Bouyahya","sequence":"additional","affiliation":[{"name":"Laboratory of Human Pathologies Biology, Faculty of Sciences, Mohammed Vth University in Rabat, Rabat 10100, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3308-2607","authenticated-orcid":false,"given":"Tarik","family":"Aanniz","sequence":"additional","affiliation":[{"name":"Medical Biotechnology Laboratory (MedBiotech), Bioinova Research Center, Medical and Pharmacy School, Mohammed V University in Rabat, Rabat 10100, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1111\/idj.12630","article-title":"Current Concepts in the Management of Periodontitis","volume":"71","author":"Kwon","year":"2021","journal-title":"Int. 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