PI3Kα是PI3K一类的四种同功酶，其作为调节酶主导细胞代谢、增殖和生存。PI3Kα的高度激活在各类癌症中都有观察到，并与恶性预后相关。遗憾的是，选择性靶向其中一种同功酶的抑制剂的研发仍然具有挑战性，临床上只有少数药物得到应用。主要困难源于ATP结合口袋上的残基在同功酶之间高度保守，该结合口袋也是抑制剂的靶点。本研究利用分子动力学和量子计算来研究选择性抑制剂alpelisib和GDC-0326进入PI3Kα的ATP结合口袋的分子特征。分子动力学使得晶体学坐标得以放松，而分子碎化与共轭帽方案和密度泛函理论计算结合可获得每个氨基酸残基与抑制剂之间的相互作用能。此外，还计算了配体在结合和未结合（自由）状态下原子电荷。结果表明，alpelisib结合的最相关残基是Ile932、Glu859、Val851、Val850、Tyr836、Met922、Ile800和Ile848，而GDC-0326结合的最重要残基是Ile848、Ile800、Ile932、Gln859、Glu849和Met922。此外，Trp780、Ile800、Tyr836、Ile848、Gln859、Val850、Val851、Ile932和Met922等残基是两种抑制剂的共同热点。总的来说，本研究结果有助于改进对分子机制选择性控制的理解，并凸显了在合理设计新药物过程中需考虑的重要相互作用。

The PI3K class I is composed of four PI3K isoforms that serve as regulatory enzymes governing cellular metabolism, proliferation, and survival. The hyperactivation of PI3Kα is observed in various types of cancer and is linked to poor prognosis. Unfortunately, the development inhibitors selectively targeting one of the isoforms remains challenging, with only few agents in clinical use. The main difficulty arises from the high conservation among residues at the ATP-binding pocket across isoforms, which also serves as target pocket for inhibitors. In this work, molecular dynamics and quantum calculations were performed to investigate the molecular features guiding the binding of selective inhibitors, alpelisib and GDC-0326, into the ATP-binding pocket of PI3Kα. While molecular dynamics allowed crystallographic coordinates to relax, the interaction eergy between each amino acid residues and inhibitors was obtained by combining the Molecular Fractionation with Conjugated Caps scheme with Density Functional Theory calculations. In addition, the atomic charge of ligands in the bound and unbound (free) was calculated. Results indicated that the most relevant residues for the binding of alpelisib are Ile932, Glu859, Val851, Val850, Tyr836, Met922, Ile800, and Ile848, while the most important residues for the binding of GDC-0326 are Ile848, Ile800, Ile932, Gln859, Glu849, and Met922. In addition, residues Trp780, Ile800, Tyr836, Ile848, Gln859 Val850, Val851, Ile932 and Met922 are common hotspots for both inhibitors. Overall, the results from this work contribute to improving the understanding of the molecular mechanisms controlling selectivity and highlight important interactions to be considered during the rational design of new agents.Communicated by Ramaswamy H. Sarma.