A Holistic In-Silico Characterization of Mortalin (HSPA9) Inhibitors from Murraya koenigii and Pogostemon cablin for TP53 Reactivation in Breast Cancer

Breast cancer, a leading cause of cancer-related deaths, is characterized by therapeutic challenges, including side effects and drug resistance. The interaction between mortalin (HSPA9) and p53, a tumor suppressor, is known to play a crucial role in cancer progression, with mortalin sequestering p53 and inhibiting its tumor-suppressive functions. This study evaluated the potential of bioactive compounds from Murraya koenigii and Pogostemon cablin as novel therapeutic agents for breast cancer through targeting the mortalin-p53 interaction. An in-silico approach combining network pharmacology, molecular docking, and molecular dynamics was employed to identify possible inhibitors of this interaction. The study identified two promising candidates: 8,8’’-biskoenigine (CID: 12967046) from M. koenigii and apigenin 7-(6’’-p-coumarylglucoside) (CID: 44257826) from P. cablin. These compounds were screened for drug-likeness, pharmacokinetics, and binding affinity to mortalin. Molecular docking and dynamics simulations demonstrated stable binding interactions with mortalin, particularly with 8,8’’-biskoenigine (-7,9 kcal/mol), which showed the strongest binding affinity and stability among the candidates. These findings highlight the potential of phytochemicals from M. koenigii and P. cablin as targeted treatments for breast cancer by modulating the mortalin-p53 signaling axis. Further experimental validation is needed to confirm their efficacy in vitro and in vivo. This research offers a promising direction for the development of plant-based compounds as effective cancer therapeutics. Keywords: Breast cancer, Mortalin, TP53, Murraya koenigii, Pogostemon cablin, 8,8’’-Biskoenigine, Apigenin derivative乳腺癌是癌症相关死亡的主要诱因之一，其临床治疗面临诸多难题，包括治疗副作用与药物耐药性。已知热激蛋白HSPA9（mortalin）与肿瘤抑制因子p53的相互作用在癌症进展中扮演关键角色——mortalin通过螯合p53并抑制其肿瘤抑制活性，促进癌症进程。本研究针对靶向mortalin-p53相互作用的新型乳腺癌治疗策略，评估了九里香（Murraya koenigii）和广藿香（Pogostemon cablin）中活性成分的治疗潜力。 本研究采用结合网络药理学、分子对接及分子动力学的计算机模拟（in silico）方法，筛选可靶向该相互作用的潜在抑制剂。研究共筛选得到两种极具潜力的候选化合物：来自九里香的8,8''-双柯恩吉因（8,8''-biskoenigine，CID: 12967046），以及来自广藿香的芹菜素7-(6''-对香豆酰葡萄糖苷)（apigenin 7-(6''-p-coumarylglucoside)，CID: 44257826）。研究团队对上述化合物进行了成药性、药代动力学特性以及与mortalin的结合亲和力筛选。 分子对接与动力学模拟结果显示，这两种化合物均可与mortalin形成稳定结合，其中8,8''-双柯恩吉因的结合亲和力最强（-7.9 kcal/mol），在所有候选化合物中表现出最优的结合稳定性。上述研究结果表明，九里香与广藿香中的植物化学成分可通过调控mortalin-p53信号轴，成为乳腺癌的靶向治疗候选方案，具备良好的开发潜力。后续仍需开展体外与体内实验验证，以确认这两种化合物的实际疗效。本研究为开发基于植物来源的高效癌症治疗药物提供了极具前景的研究方向。 关键词：乳腺癌、mortalin、TP53、九里香、广藿香、8,8''-双柯恩吉因、芹菜素衍生物