Adikusuma Wirawan, Firdayani Firdayani, Andrina Kusumastuti Siska, Nuralih Nuralih, Listiana Shelvi, Masyita Ayu, Muhammad Irham Lalu, Hodijah Siti, Zulaikha Hildayani Suci, Mugiyanto Eko
Research Center for Computing, Research Organization for Electronics and Informatics, National Research and Innovation Agency, Cibinong, Indonesia.
Department of Pharmacy, Universitas Muhammadiyah Mataram, Mataram, Indonesia.
J Egypt Natl Canc Inst. 2025 Jul 21;37(1):52. doi: 10.1186/s43046-025-00306-x.
Hepatocellular carcinoma (HCC) is a major global health concern due to its high prevalence and mortality rate. Although emodin, a natural anthraquinone derivative, has demonstrated in vitro anticancer activity against HCC cells, its specific molecular targets in HCC remain unclear.
This study used an integrated approach combining in silico network pharmacology, molecular docking, molecular dynamics simulations (MDS), and in vitro cytotoxicity assays to evaluate three emodin derivatives: emodin, 3-acetyl emodin (ACE), and 1,3,8-triacetyl emodin (TAEM). Target predictions were performed using the SwissTargetPrediction database, and HCC-related genes were retrieved from cBioPortal. Functional annotations (Gene Ontology and Reactome) identified EGFR and KIT as key targets. Docking simulations were conducted to assess binding affinities, followed by 100 ns MDS to evaluate stability. Cytotoxic effects on HepG2 cells were also assessed.
TAEM showed the strongest binding affinity to both EGFR and KIT and demonstrated the highest cytotoxicity against HepG2 cells (IC50 = 0.021 mM). MDS results indicated that the KIT-TAEM complex was the most stable among all tested combinations, supported by RMSD, RMSF, Rg, protein-ligand distance, and MM-GBSA binding energy analyses.
These findings highlight TAEM as a promising therapeutic candidate for HCC. The study demonstrates the value of integrating computational predictions with experimental validation in early-stage drug discovery.
肝细胞癌（HCC）因其高发病率和死亡率而成为全球主要的健康问题。尽管大黄素，一种天然蒽醌衍生物，已在体外显示出对肝癌细胞的抗癌活性，但其在肝癌中的具体分子靶点仍不清楚。
本研究采用了一种综合方法，结合计算机网络药理学、分子对接、分子动力学模拟（MDS）和体外细胞毒性试验，以评估三种大黄素衍生物：大黄素、3-乙酰大黄素（ACE）和1,3,8-三乙酰大黄素（TAEM）。使用SwissTargetPrediction数据库进行靶点预测，并从cBioPortal检索肝癌相关基因。功能注释（基因本体论和Reactome）确定表皮生长因子受体（EGFR）和干细胞生长因子受体（KIT）为关键靶点。进行对接模拟以评估结合亲和力，随后进行100纳秒的分子动力学模拟以评估稳定性。还评估了对HepG2细胞的细胞毒性作用。
TAEM对EGFR和KIT均显示出最强的结合亲和力，并对HepG2细胞表现出最高的细胞毒性（半数抑制浓度[IC50]=0.021毫摩尔）。分子动力学模拟结果表明，在所有测试组合中，KIT-TAEM复合物是最稳定的，这得到了均方根偏差（RMSD）、均方根波动（RMSF）、回旋半径（Rg）、蛋白质-配体距离和分子力学广义玻恩表面面积结合自由能（MM-GBSA）分析的支持。
这些发现突出了TAEM作为一种有前景的肝癌治疗候选药物。该研究证明了在早期药物发现中将计算预测与实验验证相结合的价值。
