基于MFCC方法计算表皮生长因子受体与4-苯胺基喹唑啉结合的量子力学机制  

Quantum mechanical mechanism of binding of 4-anilinoquinazoline inhibitors to the epidermal growth factor receptor based on MFCC computation

作　　者：刘金峰[1] 王雅倩[1] 张增辉[1,2,3] 何晓[1,2] 

机构地区：[1]华东师范大学化学与分子工程学院,上海200062 [2]上海纽约大学计算化学中心,上海200062 [3]纽约大学化学系,纽约10003

出　　处：《中国科技论文》2016年第18期2050-2056,共7页China Sciencepaper

基　　金：国家自然科学基金资助项目(21303057;21433004);高等学校博士学科点专项科研基金资助项目(20130076120019)

摘　　要：基于最近发展的分子碎片共轭帽(molecular fractionation with conjugate caps,MFCC)方法,表皮生长因子受体(epidermal growth factor receptor,EGFR)与其抑制剂的相互作用能得以用完整的量子力学来计算,主要包括上市的Iressa[第一代美国食品及药物管理局(Food and Drug Administration,FDA)通过的药物]和4-苯胺基喹唑啉类抑制剂Tarceva(已上市)、CI-1033与EKI-785。对EGFR的完整体系(超过5 000个原子)与4-苯胺基喹唑啉类抑制剂之间的结合作用采用了量子力学计算方法。结合体系的量子能量计算,用Hartree-Fock与密度泛函理论(density functional theory,DFT)2种方法,EGFR与Tarceva之间的相互作用能基于它们两者复合物的晶体结构得到,而其他抑制剂与EGFR的相互作用能则通过分子对接软件预测的构型进行计算。利用MFCC方法,获得了量子相互作用能谱,清楚地给出了EGFR每个氨基酸片段与4-苯胺基喹唑啉类抑制剂之间的单个相互作用能。量子研究发现,4-苯胺基喹唑啉类抑制剂与EGFR的结合通过1个氢键和静电相互作用。Iressa、Tarceva、CI-1033、EKI-785与EGFR的结合能计算值分别为-40.23、-53.09、-33.92、-31.47kcal/mol(1cal=4.184J)。研究表明,Tarceva比第一代FDA通过的药物Iressa有更强的结合能力,而CI-1033、EKI-785则表现出一般的结合作用,另外,与MFCC计算的相互作用能谱相比,有一些相互作用在力场作用能谱中被明显高估。Applying a recently developed molecular fractionation with conjugate caps （MFCC） approach, fully quantum mechanical calculation has been carried out to compute binding interactions between epidermal growth factor receptor （EGFR） and its inhibitor, mainly including Iressa （the first generation Food and Drug Administration （FAD） approved inhibitor） and other 4-anilinoquinazoline inhibitors.. Tareeva, CI-1033 and EKI-785. In this study, the entire system of EGFR and 4-anilinoquinazoline inhibitors complex with over 5 000 atoms is explicitly treated by quantum mechanics in a consistent fashion. The quantum energy calculation for the binding system is performed using Hartree-Fock and Density Functional Theory （DFT） methods. The interaction energy between EGFR and Tarceva is computed using the crystal structure of the binding complex, while others are calculated on the binding structures obtained from molecular docking. Using the MFCC approach, we obtain quantum interaction spectra that explicitly show individual interaction energies between each amino acid of EGFR and 4-anilinoquinazoline inhibitors. The present quantum study finds that 4-anilinoquinazoline inhibitors bind to EGFR through a typical hydrogen and charge-dipole interactions. The binding energies of Iressa, Tarceva, CI-1033, and EKI-785 to EGFR are calculated to be -40. 23, -53. 09, -33.92 and - 31.47 kcal/mol （1 cal= 4. 184 J）, respectively. Our study shows that Tarceva is a more potent drug than Iressa, while CI-1033, and EKI-785 show moderate potency. In addition, several individual interaction energies are overestimated in force field spectra compared with the corresponding MFCC spectra.

关 键 词：物理化学 理论与计算化学 分子碎片共轭帽 4-苯胺基喹唑啉类抑制剂 表皮生长因子受体 量子相互作用能 

分 类 号：O641.12[理学—物理化学] R96[理学—化学]