Molecular Dynamics Simulations to Investigate the Binding Mode of the Natural Product Liphagal with Phosphoinositide 3-Kinase α.
Molecular Dynamics Simulations to Investigate the Binding Mode of the Natural Product Liphagal with Phosphoinositide 3-Kinase α.
复制标题
分子动力学模拟研究天然产物 Liphagal 与磷酸肌醇 3-激酶 α 的结合模式
DOI：
10.3390/molecules21070857
复制
发表时间：
2016-06-29
期刊：
影响因子：
--
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Gao Y;Ma Y;Yang G;Li Y
磷脂酰肌醇3-激酶α (PI3Kα)是抗癌药物设计的一个有吸引力的靶点。Liphagal是从海绵中分离出来的，具有特殊的“liphagane”巯基萜类碳骨架，已被证明是PI3Kα抑制剂。通过分子对接和分子动力学模拟研究PI3Kα与liphagal结合的动力学行为，并利用分子力学/泊松-玻尔兹曼（广义Born）表面积（MM/PB(GB)SA）方法进行自由能计算和能量分解分析。结果表明，富含杂原子的脂醛芳香d环向结合位点的极区延伸，d环上的15-羟基和16-羟基与Asp810和Tyr836形成3个氢键。环己基a环向上延伸至亲脂区上部，与残基Met772、Trp780、Ile800、Ile848、Val850、Met922、Phe930、Ile932的疏水/范德华相互作用可能是脂质体与PI3Kα亲和的关键相互作用。因此，为合理设计更有效的liphagal抗PI3Kα类似物提供了一种新的策略。我们提出的PI3Kα/脂溶酶结合模式将有助于发现新的抗PI3Kα活性脂溶酶类似物。
Phosphatidylinositol 3-kinase α (PI3Kα) is an attractive target for anticancer drug design. Liphagal, isolated from the marine sponge Aka coralliphaga, possesses the special “liphagane” meroterpenoid carbon skeleton and has been demonstrated as a PI3Kα inhibitor. Molecular docking and molecular dynamics simulations were performed to explore the dynamic behaviors of PI3Kα binding with liphagal, and free energy calculations and energy decomposition analysis were carried out by use of molecular mechanics/Poisson-Boltzmann (generalized Born) surface area (MM/PB(GB)SA) methods. The results reveal that the heteroatom rich aromatic D-ring of liphagal extends towards the polar region of the binding site, and the D-ring 15-hydroxyl and 16-hydroxyl form three hydrogen bonds with Asp810 and Tyr836. The cyclohexyl A-ring projects up into the upper pocket of the lipophilic region, and the hydrophobic/van der Waals interactions with the residues Met772, Trp780, Ile800, Ile848, Val850, Met922, Phe930, Ile932 could be the key interactions for the affinity of liphagal to PI3Kα. Thus, a new strategy for the rational design of more potent analogs of liphagal against PI3Kα is provided. Our proposed PI3Kα/liphagal binding mode would be beneficial for the discovery of new active analogs of liphagal against PI3Kα.
登录
查看更多内容
DOI：
10.1016/j.bbapap.2007.10.003
发表时间：
2008-01-01
影响因子：
3.2
作者：
Marone, Romina;Cmijanovic, Vladimir;Wymann, Matthias P.
通讯作者：
Wymann, Matthias P.
影响因子：
3.9
作者：
Knight, Z. A.;Shokat, K. M.
通讯作者：
Shokat, K. M.
影响因子：
3
作者：
Duan, Y;Wu, C;Kollman, P
通讯作者：
Kollman, P
影响因子：
2.1
作者：
GASTEIGER, J;MARSILI, M
通讯作者：
MARSILI, M
影响因子：
5.2
作者：
Marion, F;Williams, DE;Andersen, RJ
通讯作者：
Andersen, RJ