癌症是一组疾病的通用术语，其定义是不受控制的细胞生长以及侵入或扩散到身体其他部位的可能性。基因和表观遗传改变破坏正常的细胞控制，导致异常细胞增殖、细胞死亡抵抗、血管发育和转移（扩散到其他器官）。在癌症发生和进展中起重要作用的几种途径之一是磷酸肌醇 3-激酶 (PI3K) 信号传导途径。此外，基因 PIK3CG 编码磷酸肌醇 3-激酶 (PI3Kγ) 的催化亚基 γ (p110γ)，PI3Kγ 是 PI3K 家族的成员。因此，在本研究中，PIK3CG通过计算方法鉴定出一种新型抑制剂来靶向抑制癌症。该研究使用基于机器学习的结合估计和对接筛选了 1015 个针对 PIK3CG 的化学片段，以选择潜在的化合物。随后，从选定的命中中生成类似物，选出414个类似物，并对其进行进一步筛选，作为最有潜力的候选物，获得了三种化合物：(a)84,332、190,213和885,387。然后通过动态模型研究蛋白质-配体复合物的稳定性和灵活性。 100 ns 模拟显示 885,387 表现出最稳定的偏差和不断产生的氢键。与其他化合物相比，当使用 MM/GBSA 技术时，885,387 表现出与蛋白质优异的结合自由能 (ΔG = -18.80 kcal/mol)。该研究确定 885,387 显示出显着的治疗潜力，并证明作为与癌症有关的 PIK3CG 靶点的可能抑制剂，进一步的实验研究是合理的。© 2024。作者，获得 Springer Nature Switzerland AG 的独家许可。

Cancer is a generic term for a group of disorders defined by uncontrolled cell growth and the potential to invade or spread to other parts of the body. Gene and epigenetic alterations disrupt normal cellular control, leading to abnormal cell proliferation, resistance to cell death, blood vessel development, and metastasis (spread to other organs). One of the several routes that play an important role in the development and progression of cancer is the phosphoinositide 3-kinase (PI3K) signaling pathway. Moreover, the gene PIK3CG encodes the catalytic subunit gamma (p110γ) of phosphoinositide 3-kinase (PI3Kγ), a member of the PI3K family. Therefore, in this study, PIK3CG was targeted to inhibit cancer by identifying a novel inhibitor through computational methods. The study screened 1015 chemical fragments against PIK3CG using machine learning-based binding estimation and docking to select the potential compounds. Later, the analogues were generated from the selected hits, and 414 analogues were selected, which were further screened, and as most potential candidates, three compounds were obtained: (a) 84,332, 190,213, and 885,387. The protein-ligand complex's stability and flexibility were then investigated by dynamic modeling. The 100 ns simulation revealed that 885,387 exhibited the steadiest deviation and constant creation of hydrogen bonds. Compared to the other compounds, 885,387 demonstrated a superior binding free energy (ΔG = -18.80 kcal/mol) with the protein when the MM/GBSA technique was used. The study determined that 885,387 showed significant therapeutic potential and justifies further experimental investigation as a possible inhibitor of the PIK3CG target implicated in cancer.© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.