Paul Jibon Kumar, Azmal Mahir, Haque Shohan Md Naimul, Mrinmoy Mohua, Newaz Been Haque Anm Shah, Talukder Omar Faruk, Ghosh Ajit
Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, 3114, Bangladesh.
Heliyon. 2025 Jan 10;11(2):e41897. doi: 10.1016/j.heliyon.2025.e41897. eCollection 2025 Jan 30.
The PI3K/AKT/mTOR pathway is central in regulating key cellular processes such as proliferation, survival, metabolism, and angiogenesis. Dysregulation of this pathway, particularly in the AKT2 isoform, is commonly observed in cancers such as breast, ovarian, and pancreatic cancers, leading to enhanced tumor progression, metastasis, and therapeutic resistance. Therefore, targeting AKT2 for inhibition is a promising strategy for cancer therapy. This study utilized molecular docking and dynamics simulations to identify natural phytochemicals that inhibit AKT2. Molecular docking results revealed that millettone (CID 442810) exhibited the highest binding affinity to AKT2, with a docking score of -9.5 kcal/mol, followed by uzarigenin (CID 92760), dihydrobiochanin A (CID 439784), and abyssinone I (CID 442152) with docking scores of -9.0 kcal/mol, -8.9 kcal/mol, and -8.7 kcal/mol respectively, outperforming the control inhibitor, ipatasertib (CID 24788740) docking score of -7.56 kcal/mol. Molecular dynamics simulations indicated that millettone, uzarigenin, and dihydrobiochanin A demonstrated strong binding affinities and stable interactions with AKT2, suggesting their potential as therapeutic agents for cancers that involve AKT2 hyperactivation. Notably, uzarigenin's superior stability, as evidenced by its lower root mean square deviation (RMSD), which measures structural stability, and solvent-accessible surface area (SASA), which indicates molecular compactness, highlights its promise as a potent inhibitor of AKT2. Future in vitro and in vivo studies will be crucial to confirm the efficacy of these inhibitors in reducing tumor progression and their potential applications. Given that AKT2 also plays a role in neuronal survival and plasticity, these compounds may have potential applications in neurodegenerative diseases such as Alzheimer's, warranting further investigation into their dual therapeutic relevance.
PI3K/AKT/mTOR信号通路在调节细胞增殖、存活、代谢和血管生成等关键细胞过程中起着核心作用。该信号通路的失调，尤其是AKT2亚型的失调，在乳腺癌、卵巢癌和胰腺癌等癌症中普遍存在，导致肿瘤进展、转移和治疗耐药性增强。因此，靶向抑制AKT2是一种很有前景的癌症治疗策略。本研究利用分子对接和动力学模拟来确定抑制AKT2的天然植物化学物质。分子对接结果显示，小米酮（CID 442810）对AKT2表现出最高的结合亲和力，对接分数为-9.5千卡/摩尔，其次是乌扎立根苷（CID 92760）、二氢生物chanin A（CID 439784）和阿比西酮I（CID 442152），对接分数分别为-9.0千卡/摩尔、-8.9千卡/摩尔和-8.7千卡/摩尔，优于对照抑制剂ipatasertib（CID 24788740）的对接分数-7.56千卡/摩尔。分子动力学模拟表明，小米酮、乌扎立根苷和二氢生物chanin A与AKT2表现出很强的结合亲和力和稳定的相互作用，表明它们作为涉及AKT2过度激活的癌症治疗药物的潜力。值得注意的是，乌扎立根苷具有卓越的稳定性，其较低的均方根偏差（RMSD，衡量结构稳定性）和溶剂可及表面积（SASA，表明分子紧密性）证明了这一点，突出了其作为AKT2有效抑制剂的前景。未来的体外和体内研究对于证实这些抑制剂在降低肿瘤进展方面的疗效及其潜在应用至关重要。鉴于AKT2在神经元存活和可塑性中也发挥作用，这些化合物可能在阿尔茨海默病等神经退行性疾病中具有潜在应用，有必要进一步研究它们的双重治疗相关性。
