在过去的几年中,癌症一直是全世界死亡的主要原因之一。在开发更有效的癌症疗法方面取得了一些进展,从而提高生存率。然而,成功治疗的预期结果尚未实现。对创新的发展有很高的要求,便宜,和使用自然资源进行有效的抗癌治疗。天然化合物由于其高度的分子多样性而被越来越多地发现并用于癌症治疗。新颖的生物功能,和最小的副作用。这些化合物可以用作化学预防剂,因为它们可以有效地抑制细胞生长,控制细胞周期进程,并阻断几种促进肿瘤的信号通路。PI3K是PI3K-Akt-mTOR途径的重要上游蛋白,并且是公认的癌症治疗靶标。本研究旨在探索小分子,天然类黄酮,viz.槲皮素,木犀草素,山奈酚,Genistein,Wogonin,Daidzein,和黄酮吡啶醇对PI3Kγ激酶活性的抑制作用。在这项研究中,绑定的姿势,相互作用的残基,分子相互作用,结合能,和解离常数进行了研究。我们的结果表明,这些类黄酮与PI3Kγ结合良好,结合强度评分和结合能范围为(-8.19至-8.97Kcal/mol)。在探索的配体中,黄酮吡啶醇的结合能最高,为-8.97Kcal/mol,码头得分(-44.40),和解离常数项,对PI3Kγ的pKd为6.58。基于以上结果,最有前途的配体的稳定性,黄酮吡啶醇,通过分子动力学模拟对PI3Kγ进行了200ns的评价,证实了稳定的黄酮吡啶醇和PI3Kγ复合物。我们的研究表明,在选定的类黄酮中,特别是黄酮吡啶醇可能作为PI3Kγ的潜在抑制剂,并且可能是抑制PI3Kγ途径的治疗替代方案,为癌症治疗的合理药物发现研究提供新的见解。
Cancer has been one of the leading causes of mortality worldwide over the past few years. Some progress has been made in the development of more effective cancer therapeutics, resulting in improved survival rates. However, the desired outcome in the form of successful treatment is yet to be achieved. There is high demand for the development of innovative, inexpensive, and effective anticancer treatments using natural resources. Natural compounds have been increasingly discovered and used for cancer therapy owing to their high molecular diversity, novel biofunctionality, and minimal side effects. These compounds can be utilized as chemopreventive agents because they can efficiently inhibit cell growth, control cell cycle progression, and block several tumor-promoting signaling pathways. PI3K is an important upstream protein of the PI3K-Akt-mTOR pathway and a well-established cancer therapeutic target. This study aimed to explore the small molecules, natural flavonoids, viz. quercetin, luteolin, kaempferol, genistein, wogonin, daidzein, and
flavopiridol for PI3Kγ kinase activity inhibition. In this study, the binding pose, interacting residues, molecular interactions, binding energies, and dissociation constants were investigated. Our results showed that these flavonoids bound well with PI3Kγ with adequate binding strength scores and binding energy ranging from (-8.19 to -8.97 Kcal/mol). Among the explored ligands,
flavopiridol showed the highest binding energy of -8.97 Kcal/mol, dock score (-44.40), and dissociation constant term, pKd of 6.58 against PI3Kγ. Based on the above results, the stability of the most promising ligand,
flavopiridol, against PI3Kγ was evaluated by molecular dynamics simulations for 200 ns, confirming the stable
flavopiridol and PI3Kγ complex. Our study suggests that among the selected flavonoids specifically
flavopiridol may act as potential inhibitors of PI3Kγ and could be a therapeutic alternative to inhibit the PI3Kγ pathway, providing new insights into rational drug discovery research for cancer therapy.