Suryono Suryono, Amien Muhammad I, Tohari Achmad I, Saputra Antonius D, Hidayat Muhammad Rf, Ramadhan Hazbina F
Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Jember, Jember, Indonesia.
Department of Cardiology and Vascular Medicine, Dr. Soebandi General Hospital, Jember, Indonesia.
Narra J. 2025 Apr;5(1):e1310. doi: 10.52225/narra.v5i1.1310. Epub 2025 Jan 8.
Cardiac fibrosis remains as the leading cause of death worldwide and is often associated with elevated levels of transforming growth factor-β 1 (TGF-β1) and galectin-3, making them potential therapeutic targets. Recent studies revealed that quercetin, myricetin, and kaempferol have the biological effect for several cardiovascular diseases. However, the investigation into this topic through molecular models and analysis remain unexplored. The aim of this study was to evaluate the potential effect of quercetin, myricetin, and kaempferol which targeted TGF-β1 and galectin-3. In this study, quercetin, myricetin, and kaempferol roled as the tested ligands. Subsequently, colchicine and native ligand acted as control ligands that were screened through molecular docking against TGF-β1 and galectin-3 using AutoDock tools to identify the potential inhibitor. The stability of ligand- receptor complexes was assessed through molecular dynamic (MD) simulations using NMAD. Absorption, Distribution, Metabolism, Excretion and toxicity (ADMET) prediction were also performed using ADMETlab 2.0. Molecular docking analysis revealed that quercetin, myricetin, and kaempferol exhibited strong binding affinity which are -8.9 kcal/mol, -8.5 kcal/mol, -7.6 kcal/mol respectively with TGF-β1, and -7.5 kcal/mol, -7.0 kcal/mol, -5.7 kcal/mol respectively with galetcin-3; low inhibition constant (Ki); and stable interaction with the active sites of TGF-β1 and galectin-3. MD simulations confirmed the stability and compactness of the ligand-receptor complexes. ADMET analysis also showed high Plasma Protein Binding (PPB) values (quercetin: 95%, myricetin: 92%, and kaempferol: 97%) and moderate clearance values (quercetin: 8.284%, myricetin, and 7.716%, kaempferol: 6.868%) for the tested compounds. In conclusion, the in silico analyses suggested that quercetin, myricetin, and kaempferol are promising for cardiac fibrosis therapies by inhibiting TGF-β1 and galectin-3.
心脏纤维化仍然是全球主要的死亡原因，并且常常与转化生长因子-β1（TGF-β1）和半乳糖凝集素-3水平升高相关，这使得它们成为潜在的治疗靶点。最近的研究表明，槲皮素、杨梅素和山奈酚对几种心血管疾病具有生物学效应。然而，通过分子模型和分析对该主题的研究仍未得到探索。本研究的目的是评估槲皮素、杨梅素和山奈酚对TGF-β1和半乳糖凝集素-3的潜在作用。在本研究中，槲皮素、杨梅素和山奈酚作为受试配体。随后，秋水仙碱和天然配体作为对照配体，使用AutoDock工具通过与TGF-β1和半乳糖凝集素-3进行分子对接来筛选潜在抑制剂。使用NMAD通过分子动力学（MD）模拟评估配体-受体复合物的稳定性。还使用ADMETlab 2.0进行吸收、分布、代谢、排泄和毒性（ADMET）预测。分子对接分析表明，槲皮素、杨梅素和山奈酚分别与TGF-β1表现出较强的结合亲和力，分别为-8.9千卡/摩尔、-8.5千卡/摩尔、-7.6千卡/摩尔，与半乳糖凝集素-3分别为-7.5千卡/摩尔、-7.0千卡/摩尔、-5.7千卡/摩尔；抑制常数（Ki）较低；并且与TGF-β1和半乳糖凝集素-3的活性位点有稳定的相互作用。MD模拟证实了配体-受体复合物的稳定性和紧密性。ADMET分析还显示受试化合物具有较高的血浆蛋白结合（PPB）值（槲皮素：95%，杨梅素：92%，山奈酚：97%）和中等的清除率值（槲皮素：8.284%，杨梅素：7.716%，山奈酚：6.868%）。总之，计算机模拟分析表明，槲皮素、杨梅素和山奈酚通过抑制TGF-β1和半乳糖凝集素-3在心脏纤维化治疗方面具有前景。
