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挑战，包括治疗相关不良反应与多药耐药问题。热休克蛋白HSPA9（mortalin, HSPA9）与肿瘤抑制因子p53之间的相互作用，已被证实对癌症进展至关重要：mortalin可通过螯合p53并抑制其肿瘤抑制活性，进而推动癌症进展。本研究以靶向mortalin-p53相互作用为目标，评估了九里香（Murraya koenigii）与广藿香（Pogostemon cablin）来源的生物活性化合物作为新型乳腺癌治疗药物的潜力。研究采用结合网络药理学、分子对接与分子动力学的虚拟实验（in silico）方法，筛选该相互作用的潜在抑制剂。最终鉴定出两种极具开发前景的候选化合物：分别来源于九里香的8,8''-双柯文宁（CID: 12967046），以及来源于广藿香的芹菜素7-(6''-对香豆酰葡萄糖苷)（CID: 44257826）。研究对上述化合物进行了成药性、药代动力学特征及与mortalin结合亲和力的筛选与评估。分子对接与分子动力学模拟结果显示，两类化合物均可与mortalin形成稳定的结合相互作用，其中8,8''-双柯文宁的结合亲和力最强（-7.9 kcal/mol），在所有候选化合物中表现出最优的结合稳定性。本研究结果表明，来源于九里香与广藿香的植物化学成分，可通过调控mortalin-p53信号轴，成为极具潜力的乳腺癌靶向治疗候选方案。后续仍需开展体外与体内实验验证，以确认这些化合物的实际治疗疗效。本研究为开发基于植物来源的高效癌症治疗药物指明了极具前景的研发方向。

关键词：乳腺癌、mortalin、TP53、九里香（Murraya koenigii）、广藿香（Pogostemon cablin）、8,8''-双柯文宁、芹菜素衍生物