{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:58:43Z","timestamp":1787029123792,"version":"build-2736575974"},"reference-count":45,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,16]],"date-time":"2025-11-16T00:00:00Z","timestamp":1763251200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Macao Polytechnic University Foundation","award":["RP\/FCA 07\/2022"],"award-info":[{"award-number":["RP\/FCA 07\/2022"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Acne vulgaris is a prevalent inflammatory disease of the pilosebaceous unit in which Cutibacterium acnes (C. acnes) contributes to lesion initiation and persistence, supporting antibacterial interventions as a component of clinical management. Given the essential role of the 50S large ribosomal subunit\u2014particularly 23S rRNA sites in the peptidyl transferase center and nascent peptide exit tunnel\u2014in C. acnes protein synthesis and viability, targeting the 50S offers an effective path to lead discovery for acne treatment. Here, we present an integrated computational\u2013experimental workflow to identify anti-C. acnes candidates from a 186,659-compound natural product library. Curated 50S\/23S ligands trained and validated two ML-QSAR regression models built on different molecular fingerprints (MACCS keys and PubChem 2D) to predict anti-C. acnes activity and rapidly triage the library. Compounds were further screened by ADMET filtering and structure-based docking to 23S rRNA pockets, followed by cluster and interaction analysis. Among six experimental hits, three compounds exhibited MICs against C. acnes of \u22648 \u03bcg\/mL, with tripterin, a pentacyclic triterpenoid, being the most potent (0.5\u20132 \u03bcg\/mL across two acne-relevant strains). Collectively, these results indicate that a 50S ribosomal-focused, multistage computational screening workflow, integrated with in vitro assays, efficiently prioritizes compounds with quantifiable anti-C. acnes activity across a broad range of natural products.<\/jats:p>","DOI":"10.3390\/molecules30224433","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T12:33:04Z","timestamp":1763469184000},"page":"4433","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrated Machine Learning and Structure-Based Virtual Screening Identifies Natural Product Targeting 50S Ribosome Inhibitory Activity Against Cutibacterium acnes"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5402-0221","authenticated-orcid":false,"given":"Jixing","family":"Liu","sequence":"first","affiliation":[{"name":"Centre for Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao 999078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2687-741X","authenticated-orcid":false,"given":"Henry H. Y.","family":"Tong","sequence":"additional","affiliation":[{"name":"Centre for Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao 999078, China"},{"name":"Faculty of Health Sciences and Sports, Macao Polytechnic University, Macao 999078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2825-0576","authenticated-orcid":false,"given":"Hang","family":"Zheng","sequence":"additional","affiliation":[{"name":"School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4668-034X","authenticated-orcid":false,"given":"Miriam Iun Fan","family":"Lei","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences and Sports, Macao Polytechnic University, Macao 999078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4434-6172","authenticated-orcid":false,"given":"Shu","family":"Li","sequence":"additional","affiliation":[{"name":"Centre for Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao 999078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2055","DOI":"10.1001\/jama.2021.17633","article-title":"Management of acne vulgaris: A review","volume":"326","author":"Eichenfield","year":"2021","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/s13555-023-01079-8","article-title":"The microbiome and acne: Perspectives for treatment","volume":"14","author":"Dessinioti","year":"2024","journal-title":"Dermatol. 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