磷酸肌醇 3 激酶 (PI3 K) 是多种癌症中细胞信号转导的关键调节因子。特别是，编码 p110α 催化亚基的 PIK3CA 基因的突变驱动致癌信号传导，使其成为有吸引力的治疗靶点。我们的研究对乳腺癌、子宫内膜癌、结肠癌和卵巢癌的 31 个 PIK3CA 突变进行了计算机探索，评估了它们对 PI3Kα 抑制剂反应的影响，识别了潜在的无毒抑制剂，并阐明了它们对蛋白质稳定性和灵活性的影响。具体来说，我们观察到这些突变诱导 PI3 K 蛋白的稳定性和灵活性发生显着变化。通过分子对接分析，我们评估了所选抑制剂与 PI3 K 蛋白之间的结合相互作用。配体的过滤涉及计算化学描述符、结合 Veber 和 Lipinski 规则以及 IC50 值和毒性预测。这一过程将 1394 种配体的初始数据集减少为 12 种潜在的无毒抑制剂，然后根据其理化性质选择了四种在临床试验中具有显着生物活性的参考抑制剂。该分析揭示了 Lig5 的卓越性能，与 pictilisib 等已建立的参考抑制剂相比，表现出卓越的亲和力和特异性。 Lig5 与 PI3 K 蛋白形成强大的结合相互作用，表明其作为针对 PI3 K 驱动的癌症的高效治疗剂的潜力。此外，分子动力学模拟为 Lig5 的稳定性及其与 PI3 K 超过 100 ns 的相互作用提供了宝贵的见解。这些模拟支持了 Lig5 作为多功能抑制剂的潜力，能够有效地针对 PI3 K 的各种突变谱，从而减轻与当前抑制剂通常相关的耐药性和毒性相关问题。© 作者 2024。

Phosphoinositide-3-kinases (PI3 K) are pivotal regulators of cell signaling implicated in various cancers. Particularly, mutations in the PIK3CA gene encoding the p110α catalytic subunit drive oncogenic signaling, making it an attractive therapeutic target. Our study conducted in silico exploration of 31 PIK3CA mutations across breast, endometrial, colon, and ovarian cancers, assessing their impacts on response to PI3Kα inhibitors and identifying potential non-toxic inhibitors and also elucidating their effects on protein stability and flexibility. Specifically, we observed significant alterations in the stability and flexibility of the PI3 K protein induced by these mutations. Through molecular docking analysis, we evaluated the binding interactions between the selected inhibitors and the PI3 K protein. The filtration of ligands involved calculating chemical descriptors, incorporating Veber and Lipinski rules, as well as IC50 values and toxicity predictions. This process reduced the initial dataset of 1394 ligands to 12 potential non-toxic inhibitors, and four reference inhibitors with significant biological activity in clinical trials were then chosen based on their physico-chemical properties. This analysis revealed Lig5's exceptional performance, exhibiting superior affinity and specificity compared to established reference inhibitors such as pictilisib. Lig5 formed robust binding interactions with the PI3 K protein, suggesting its potential as a highly effective therapeutic agent against PI3 K-driven cancers. Furthermore, molecular dynamics simulations provided valuable insights into Lig5's stability and its interactions with PI3 K over 100 ns. These simulations supported Lig5's potential as a versatile inhibitor capable of effectively targeting various mutational profiles of PI3 K, thereby mitigating issues related to resistance and toxicity commonly associated with current inhibitors.© The Author(s) 2024.