{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T05:08:23Z","timestamp":1778821703123,"version":"3.51.4"},"reference-count":40,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Shenzhen Science and Technology Program","award":["JCYJ20240813152313019 and JCYJ20250604150048016"],"award-info":[{"award-number":["JCYJ20240813152313019 and JCYJ20250604150048016"]}]},{"DOI":"10.13039\/501100001809","name":"The Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82374531"],"award-info":[{"award-number":["82374531"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Immune evasion remains a critical barrier to effective hepatocellular carcinoma (HCC) therapy. Lactate dehydrogenase A (LDHA) drives lactate accumulation and histone lysine lactylation (Kla), reshaping the immunosuppressive microenvironment, while bromodomain-containing protein 4 (BRD4) sustains B7-H3 transcription via super-enhancer occupancy. Despite their synergistic roles in the lactate\u2013Kla\u2013B7-H3 immunosuppressive axis, no dual-target inhibitor simultaneously engaging both proteins has been reported. This study aimed to discover dual LDHA\/BRD4 inhibitors from natural product libraries using an integrated AI-driven computational pipeline. Methods: We established a multi-tier virtual screening cascade comprising Lipinski\/QED drug-likeness filtration, DiffDock-based AI docking, QuickVina binding energy validation, PLIP interaction profiling, 200 ns all-atom molecular dynamics simulations, MM-GBSA binding free energy calculations, and density functional theory analysis. Natural product libraries from COCONUT and CMNPD databases (84,730 compounds post-filtration) were screened against both targets. Results: High-throughput DiffDock screening identified 11 dual-target hits, from which CNP0038114.1 and CMNPD16582 emerged as prioritized lead candidates. All four protein\u2013ligand complexes maintained structural stability throughout MD simulations, with MM-GBSA binding free energies ranging from \u221227.24 to \u221232.45 kcal\/mol, predominantly driven by van der Waals interactions. DFT calculations revealed distinct electronic profiles: CNP0038114.1 exhibited a narrow HOMO\u2013LUMO gap (2.718 eV) favoring charge-transfer reactivity, whereas CMNPD16582 displayed a larger gap (4.822 eV), suggesting superior chemical stability. Conclusions: This computational study furnishes two novel natural product leads for targeting the lactate\u2013Kla\u2013B7-H3 immunosuppressive axis in HCC, establishing a generalizable AI-driven workflow for dual-target inhibitor discovery.<\/jats:p>","DOI":"10.3390\/ph19050736","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T14:05:46Z","timestamp":1778162746000},"page":"736","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Computational Discovery of Dual-Target LDHA\/BRD4 Inhibitors Targeting the Lactate\u2013Kla\u2013B7-H3 Immunosuppressive Axis Through AI-Driven Virtual Screening"],"prefix":"10.3390","volume":"19","author":[{"given":"Ruiqi","family":"Zhao","sequence":"first","affiliation":[{"name":"The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Shenzhen 518033, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengyao","family":"Han","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510405, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bei","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Shenzhen 518033, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengqing","family":"Ma","sequence":"additional","affiliation":[{"name":"Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao 999078, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4758-0060","authenticated-orcid":false,"given":"Xiaozhou","family":"Zhou","sequence":"additional","affiliation":[{"name":"The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Shenzhen 518033, China"},{"name":"Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao 999078, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jialing","family":"Sun","sequence":"additional","affiliation":[{"name":"The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Shenzhen 518033, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Gao, Y., Li, W., Huang, X., Lyu, Y., and Yue, C. 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