{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T01:12:03Z","timestamp":1788743523727,"version":"build-2803163510"},"reference-count":44,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Thailand Science research and Innovation Fund Chulalongkorn University","award":["HEA_FF_69_062_2300_018"],"award-info":[{"award-number":["HEA_FF_69_062_2300_018"]}]},{"award":["HEA_FF_69_062_2300_018"],"award-info":[{"award-number":["HEA_FF_69_062_2300_018"]}],"id":[{"id":"https:\/\/ror.org\/028wp3y58","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004704","name":"National Research Council of Thailand","doi-asserted-by":"crossref","award":["N42A650231"],"award-info":[{"award-number":["N42A650231"]}],"id":[{"id":"10.13039\/501100004704","id-type":"DOI","asserted-by":"crossref"}]},{"award":["N42A650231"],"award-info":[{"award-number":["N42A650231"]}],"id":[{"id":"https:\/\/ror.org\/018wfhg78","id-type":"ROR","asserted-by":"publisher"}]},{"name":"90th Anniversary of Chulalongkorn University Fund","award":["GCUGR1125671132D"],"award-info":[{"award-number":["GCUGR1125671132D"]}]},{"award":["GCUGR1125671132D"],"award-info":[{"award-number":["GCUGR1125671132D"]}],"id":[{"id":"https:\/\/ror.org\/028wp3y58","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Fundamental Fund of Khon Kaen University"},{"name":"NSTDA Supercomputer Center"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells when the spike receptor-binding domain (RBD) engages angiotensin-converting enzyme 2 (ACE2). Cannabinoid scaffolds have recently been reported to bind S1\/RBD, block spike-mediated membrane fusion, and modulate host inflammatory pathways, making them attractive candidates for entry inhibition. Here, we applied an integrated computational pipeline to prioritize cannabis-derived compounds as interfacial blockers of the RBD\u2013ACE2 complex across variants. Eleven phytocannabinoids were docked into the wild-type (WT) RBD\u2013ACE2 interface, identifying three cavities, with ligands preferentially occupying pocket 1. Complexes were subjected to triplicate 200 ns all-atom molecular dynamics (MD) simulations for WT, Delta, and Omicron BA.1 RBD\u2013ACE2. Binding energetics were quantified using molecular mechanics\/generalized Born surface area (MM\/GBSA) and solvated interaction energy (SIE), and per-residue contributions were analyzed together with solvent-accessible surface area (SASA) and residue interaction networks. Among all compounds, cannabidiol (CBD) and cannabinol (CBN) were the only ligands that remained stably bound in pocket 1 for all variants. CBN showed the most favorable ligand\u2013complex binding in WT, whereas CBD preserved favorable binding in Omicron BA.1 despite reduced interface burial, indicating that van der Waals\/electrostatic complementarity and solvation, rather than surface coverage alone, govern affinity. Both ligands weakened modeled RBD\u2013ACE2 binding by perturbing hot-spot residues centered on Y505 or N501Y in RBD and E37, A387, and R393 in ACE2. Overall, our results highlight CBD and CBN as tractable, variant-spanning interface disruptors and illustrate how MD-based free-energy calculations can support computational drug discovery against evolving viral protein\u2013protein interfaces.<\/jats:p>","DOI":"10.3390\/molecules31081253","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T07:55:12Z","timestamp":1775807712000},"page":"1253","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Molecular Dynamics and Solvated Interaction Energy Prioritize Cannabidiol and Cannabinol as Variant-Spanning SARS-CoV-2 RBD\u2013ACE2 Interface Blockers"],"prefix":"10.3390","volume":"31","author":[{"given":"Napat","family":"Kongtaworn","sequence":"first","affiliation":[{"name":"Program in Bioinformatics and Computational Biology, College of Interdisciplinary and Integrative Studies, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0968-3445","authenticated-orcid":false,"given":"Silpsiri","family":"Sinsulpsiri","sequence":"additional","affiliation":[{"name":"Center of Excellence in Biocatalyst and Sustainable Biotechnology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chonnikan","family":"Hanpaibool","sequence":"additional","affiliation":[{"name":"Center of Excellence in Biocatalyst and Sustainable Biotechnology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0035-0070","authenticated-orcid":false,"given":"Phornphimon","family":"Maitarad","sequence":"additional","affiliation":[{"name":"Research Center of Nano Science and Technology, Shanghai University, Shanghai 200444, China"},{"name":"Emerging Industries Institute, Shanghai University, Jiaxing 314006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4389-334X","authenticated-orcid":false,"given":"Panupong","family":"Mahalapbutr","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7402-3235","authenticated-orcid":false,"given":"Thanyada","family":"Rungrotmongkol","sequence":"additional","affiliation":[{"name":"Program in Bioinformatics and Computational Biology, College of Interdisciplinary and Integrative Studies, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Center of Excellence in Biocatalyst and Sustainable Biotechnology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"ftaa042","DOI":"10.1093\/femspd\/ftaa042","article-title":"Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a newly emerged pathogen: An overview","volume":"78","author":"Rathore","year":"2020","journal-title":"Pathog. 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