{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T05:04:42Z","timestamp":1789275882353,"version":"build-2803163510"},"reference-count":34,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82574882"],"award-info":[{"award-number":["82574882"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82074286"],"award-info":[{"award-number":["82074286"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82574882"],"award-info":[{"award-number":["82574882"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82074286"],"award-info":[{"award-number":["82074286"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Open Fund Project of the NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor","award":["NHCDP2024005"],"award-info":[{"award-number":["NHCDP2024005"]}]},{"name":"Drug Efficacy and Health Risk Assessment Key Laboratory of Zhenjiang","award":["SS2024006"],"award-info":[{"award-number":["SS2024006"]}]},{"DOI":"10.13039\/501100004608","name":"Natural Science Foundation of Jiangsu Province","doi-asserted-by":"crossref","award":["BK20251851"],"award-info":[{"award-number":["BK20251851"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Zhenjiang Science and technology development Foundation","award":["SH2025069"],"award-info":[{"award-number":["SH2025069"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: The programmed death-1\/programmed death-ligand 1 (PD-1\/PD-L1) immune checkpoint is a key therapeutic target in cancer immunotherapy, but small-molecule inhibition remains challenging due to its shallow and dynamic interaction interface. This study aimed to develop an artificial intelligence (AI)-guided workflow to identify novel small-molecule inhibitors targeting the PD-L1 dimer interface. Methods: A combined computational and experimental approach was established. A support vector regression-genetic algorithm (SVR-GA) model was trained on a dataset of 1385 known PD-L1 inhibitors to predict activity and guide molecular generation. From 470 AI-generated candidates, docking and molecular dynamics (MD) simulations were used for virtual screening. Selected compounds were synthesized and evaluated for PD-1\/PD-L1 binding disruption using homogeneous time-resolved fluorescence (HTRF) assays. Cytotoxicity was tested in MDA-MB-231 and 4T1 cell monocultures, and in vivo efficacy was assessed in an immunocompetent 4T1 tumor model. Results: Two hits, PD-L1-Ser and PD-L1-Ser-OEt, were identified. Both disrupted PD-1\/PD-L1 binding in HTRF assays, with PD-L1-Ser-OEt showing higher potency (IC50 = 0.2068 \u03bcM). Both compounds exhibited limited direct cytotoxicity in cancer cell monocultures, suggesting an immune-mediated mechanism. In the 4T1 syngeneic mouse model, both inhibitors suppressed tumor growth without causing body weight loss. PD-L1-Ser-OEt demonstrated superior antitumor efficacy and elevated serum levels of IFN-\u03b3 and IL-4. Conclusions: This AI-guided workflow combining machine-learning-based molecular generation with structure validation is feasible for discovering PD-L1 dimer-interface inhibitors. PD-L1-Ser-OEt represents a promising lead compound for further development as an immune checkpoint inhibitor.<\/jats:p>","DOI":"10.3390\/ph19091439","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T09:09:40Z","timestamp":1789117780000},"page":"1439","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated Machine Learning and Molecular Simulation-Guided Discovery of Novel Small-Molecule PD-L1 Inhibitors"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5566-817X","authenticated-orcid":false,"given":"Mengjie","family":"Rui","sequence":"first","affiliation":[{"name":"School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China"},{"name":"Engineering and Technology Institute of Jiangsu University, Zhenjiang 212013, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Wenyan","family":"Liang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Kexin","family":"Chu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Jiukun","family":"Yuan","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"given":"Ruojing","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"given":"Hangyu","family":"Dong","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9628-1331","authenticated-orcid":false,"given":"Chunlai","family":"Feng","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China"},{"name":"Department of Obstetrics, Affiliated Hospital of Jiangsu University, No.438 Jiefang Road, Zhenjiang 212001, China"},{"name":"Research Center for Intelligent Healthcare and Digital Health Technology, Affiliated Yixing People\u2019s Hospital of Jiangsu University, Wuxi 214205, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/978-981-15-3266-5_3","article-title":"Roles of PD-1\/PD-L1 Pathway: Signaling, Cancer, and Beyond","volume":"Volume 1248","author":"Xu","year":"2020","journal-title":"Regulation of Cancer Immune Checkpoints"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Parvez, A., Choudhary, F., Mudgal, P., Khan, R., Qureshi, K.A., Farooqi, H., and Aspatwar, A. 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