College of Life Sciences, Northwest Normal University, Lanzhou 730070, China.
Molecules. 2022 Aug 9;27(16):5071. doi: 10.3390/molecules27165071.
Pictilisib (GDC-0941) is a well-known dual inhibitor of class I PI3K and mTOR and is presently undergoing phase 2 clinical trials for cancer treatment. The present work investigated the dynamic behaviors and interaction mechanism between GDC-0941 and human serum albumin (HSA). Molecular docking and MD trajectory analyses revealed that GDC-0941 bound to HSA and that the binding site was positioned in subdomain IIA at Sudlow's site I of HSA. The fluorescence intensity of HSA was strongly quenched by GDC-0941, and results showed that the HSA-GDC-0941 interaction was a static process caused by ground-state complex formation. The association constant of the HSA-GDC-0941 complex was approximately 10 M, reflecting moderate affinity. Thermodynamic analysis conclusions were identical with MD simulation results, which revealed that van der Waals interactions were the vital forces involved in the binding process. CD, synchronous, and 3D fluorescence spectroscopic results revealed that GDC-0941 induced the structural change in HSA. Moreover, the conformational change of HSA affected its molecular sizes, as evidenced by AFM. This work provides a useful research strategy for exploring the interaction of GDC-0941 with HSA, thus helping in the understanding of the transport and delivery of dual inhibitors in the blood circulation system.
皮克替利昔布（GDC-0941）是一种著名的 I 类 PI3K 和 mTOR 双重抑制剂，目前正在进行癌症治疗的 2 期临床试验。本工作研究了 GDC-0941 与人血清白蛋白（HSA）之间的动态行为和相互作用机制。分子对接和 MD 轨迹分析表明，GDC-0941 与 HSA 结合，结合位点位于 HSA 的亚结构域 IIA 中的 Sudlow 位点 I。GDC-0941 强烈猝灭 HSA 的荧光强度，结果表明 HSA-GDC-0941 相互作用是由基态复合物形成引起的静态过程。HSA-GDC-0941 复合物的结合常数约为 10 M，反映出中等亲和力。热力学分析结论与 MD 模拟结果一致，表明范德华相互作用是结合过程中的重要力。CD、同步和 3D 荧光光谱结果表明 GDC-0941 诱导 HSA 的结构变化。此外，HSA 的构象变化影响其分子大小，这一点可以通过 AFM 得到证明。这项工作为探索 GDC-0941 与 HSA 的相互作用提供了有用的研究策略，有助于理解双重抑制剂在血液循环系统中的转运和递送。
