{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T08:46:13Z","timestamp":1785833173073,"version":"3.56.0"},"reference-count":72,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001459","name":"the Jeju RISE center","doi-asserted-by":"publisher","award":["2026-RISE-17-001"],"award-info":[{"award-number":["2026-RISE-17-001"]}],"id":[{"id":"10.13039\/501100001459","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Dysregulated melanogenesis underpins numerous hyperpigmentation disorders. Gancidin W, a naturally occurring diketopiperazine with diverse biological activities, has attracted interest as a potential bioactive compound; however, its role in melanogenesis remains largely unexplored. This study aimed to evaluate the anti-melanogenic potential of Gancidin W through an integrated experimental and computational approach. Methods: Network pharmacology analysis was performed to investigate the potential molecular mechanisms of Gancidin W against hyperpigmentation. The cellular effects of Gancidin W were evaluated in \u03b1-MSH-stimulated B16F10 melanoma cells by assessing intracellular tyrosinase activity, melanin content, and cytotoxicity. Furthermore, density functional theory (DFT) calculations, molecular dynamics (MD) simulations, MM\/GBSA binding free-energy analysis, and relative binding free-energy (RBFE) calculations were conducted to investigate the molecular interactions of Gancidin W and its structurally related analogue Maculosin with human tyrosinase-related protein 1 (hTYRP1). Results: Network pharmacology analysis predicted potential targets and signaling pathways involved in melanogenesis regulation. Gancidin W reduced intracellular tyrosinase activity by 34.54% and melanin content by 25.09% without cytotoxic effects. Multiscale computational analyses demonstrated stable interactions of Gancidin W within the hTYRP1 active site and favorable binding energetics (\u0394Gbind = \u221228.77 \u00b1 0.75 kcal\/mol). Compared with Maculosin, Gancidin W exhibited a more favorable binding profile, as supported by MM\/GBSA and RBFE analyses, consistent with the inhibitory effects observed in the cellular assays. Conclusions: Gancidin W exhibits anti-melanogenic potential, and multiscale computational analyses provide molecular insights into its interaction with hTYRP1. These findings support further investigation of Gancidin W as a potential natural depigmenting agent for hyperpigmentation-related disorders.<\/jats:p>","DOI":"10.3390\/ph19081191","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T13:53:31Z","timestamp":1785333211000},"page":"1191","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Computational and Cellular Evaluation of the Anti-Melanogenic Potential of Gancidin W: Integrating Network Pharmacology and Free-Energy Analyses"],"prefix":"10.3390","volume":"19","author":[{"given":"Yang","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Chemistry and Cosmetics, Jeju National University, Jeju 63243, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3000-7989","authenticated-orcid":false,"given":"Chang-Gu","family":"Hyun","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Cosmetics, Jeju National University, Jeju 63243, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3641","DOI":"10.1021\/cr200398y","article-title":"2,5-Diketopiperazines: Synthesis, reactions, medicinal chemistry, and bioactive natural products","volume":"112","author":"Borthwick","year":"2012","journal-title":"Chem. 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