发表机构
Department of Biological Sciences, School of Basic and Applied Sciences, Dayananda Sagar University; School of Engineering, Dayananda Sagar University; Prescience Insilico Private Limited（戴扬达·萨加尔大学基础与应用科学学院生物学系; 戴扬达·萨加尔大学工程学院; 普雷西恩斯因西里科私人有限公司）
机构由 AI 辅助整理，请以论文原文为准。AI 中文总结
本研究通过分子对接和MLSD等方法，发现番木瓜叶的Carpaine和Rutin可分别通过加性和变构效应抑制BCL-2和WWP1，与硼替佐米联用增强抗癌潜力。
AI 中文摘要
癌症仍然是全球主要的健康问题，原因在于化疗耐药性和高剂量治疗带来的毒性。为了克服这些挑战，针对癌症进展中关键蛋白的新治疗策略至关重要。本研究评估了来自番木瓜叶的两种植物化学物质 Carpaine（Car）和 Rutin（Rut），通过靶向 B 细胞淋巴瘤 2（BCL-2）和含 WW 结构域蛋白 1（WWP1）来增强癌症治疗的潜力。我们使用分子对接、多配体同时对接（MLSD）、分子动力学（MD）模拟和 MMPBSA 分析评估了它们的加性、变构和协同效应。Car 和 Rut 通过结合同一口袋内的不同区域，对 BCL-2 表现出加性效应。MLSD 显示结合亲和力改善至 -13.13 ± 0.08 kcal/mol，优于单个配体或商业抑制剂 Venetoclax。对于 WWP1，Car 结合在 H 位点附近，Rut 结合在 Le 位点附近，表现出变构效应，使 Car 在 MLSD 中的结合亲和力增加至 -15.59 ± 0.39 kcal/mol。此外，Rut 与硼替佐米（Bort）联合使用显示出与 WWP1 的协同相互作用。结合能分别为 Bort 的 -7.64 ± 0.156 kcal/mol、Rut 的 -10.26 ± 0.07 kcal/mol 和 MLSD 的 -15.59 ± 0.39 kcal/mol，表明通过协同作用形成了更稳定的复合物。这些结果表明 Car 和 Rut，特别是与 Bort 联合使用时，是针对癌症相关蛋白 BCL-2 和 WWP1 的有前景的候选药物。需要进一步的实验验证以探索其治疗潜力。
英文摘要
Cancer remains a major global health concern due to chemotherapy resistance and toxicity from high-dose treatments. To overcome these challenges, new therapeutic strategies targeting key proteins in cancer progression are essential. This study evaluates two phytochemicals, Carpaine (Car) and Rutin (Rut), from Carica papaya leaves, for their potential in enhancing cancer therapy by targeting B-cell lymphoma 2 (BCL-2) and WW domain-containing protein 1 (WWP1) proteins. We assessed their additive, allosteric, and synergistic effects using molecular docking, multi-ligand simultaneous docking (MLSD), molecular dynamics (MD) simulations, and MMPBSA analysis. Car and Rut showed an additive effect on BCL-2 by binding at distinct regions within the same pocket. MLSD revealed an improved binding affinity of -13.13 +/- 0.08 kcal/mol, compared with individual ligands or the commercial inhibitor Venetoclax. For WWP1, Car bound near the H-site and Rut near the Le-site, exhibiting an allosteric effect that increased Car's binding affinity in MLSD to -15.59 +/- 0.39 kcal/mol. Furthermore, Rut combined with bortezomib (Bort) demonstrated a synergistic interaction with WWP1. Binding energies were -7.64 +/- 0.156 kcal/mol for Bort, -10.26 +/- 0.07 kcal/mol for Rut, and -15.59 +/- 0.39 kcal/mol for MLSD, suggesting a more stable complex through synergy. These results suggest Car and Rut, particularly in combination with Bort, as promising candidates against cancer-related proteins BCL-2 and WWP1. Further experimental validation is warranted to explore their therapeutic potential.
Comments\c{opyright} 2025 The Author(s). Published by Elsevier B.V
Journal refPhytomedicine Plus, Volume 5, Issue 3, August 2025, 100829
DOI：10.1016/j.phyplu.2025.100829
