Conformational analysis and parallel QM/MM X-ray refinement of protein bound anti-Alzheimer drug donepezil.
Conformational analysis and parallel QM/MM X-ray refinement of protein bound anti-Alzheimer drug donepezil.
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蛋白结合的抗alzheimer药物多奈替齐的构象分析和平行QM/MM X射线细化。
DOI：
10.1021/ct300957x
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发表时间：
2013-12-03
影响因子：
5.5
通讯作者：
Merz, Kenneth M., Jr.
中科院分区：
文献类型：
--
作者：
Fu, Zheng;Li, Xue;Miao, Yipu;Merz, Kenneth M., Jr.
在过去的几十年里，多奈哌齐与乙酰胆碱酯酶(AChE)的识别和关联已被广泛研究，因为前者被用作轻度阿尔茨海默病的姑息治疗。在这里，我们研究了多奈哌齐的构象性质，并使用量子力学/分子力学(QM/MM)X射线精细化工具重新研究了多奈哌齐-AChE的晶体结构。采用M06密度泛函和MP2/完全基组(CBS)方法，采用Aug-cc-pVXZ(X=D和T)基组，对多奈哌齐的构象能面进行了研究。多奈哌齐-乙酰胆碱酯酶复合体(PDB 1EVE)还通过基于内部从头算代码QM/MM的并行X射线精化方法进行了重新精化，该方法利用分布式SCF算法中的消息传递接口(MPI)通过并行化来加速计算。在QM/MM重新精制的多奈哌齐结构中，改善了先前存在于PDB沉积几何构型中的坐标误差，从而改进了多奈哌齐与位于AChE活性中心峡谷中的芳香族侧链之间相互作用的建模。作为重新提纯的结果，与原始的PDB结构相比，多奈哌齐的构象应变能降低了93%。本工作的结果为继续开发更有效和姑息性的阿尔茨海默病治疗方法提供了更详细的结构和生化抑制剂-AChE信息。
The recognition and association of donepezil with acetylcholinesterase (AChE) has been extensively studied in the past several decades because of the former’s use as a palliative treatment for mild Alzheimer disease. Herein we examine the conformational properties of donepezil and we re-examine the donepezil-AChE crystal structure using combined quantum mechanical/molecular mechanical (QM/MM) X-ray refinement tools. Donepezil’s conformational energy surface was explored using the M06 suite of density functionals and with the MP2/complete basis set (CBS) method using the aug-cc-pVXZ (X = D and T) basis sets. The donepezil-AChE complex (PDB 1EVE) was also re-refined through a parallel QM/MM X-ray refinement approach based on an in-house ab initio code QUICK, which uses the message passing interface (MPI) in a distributed SCF algorithm to accelerate the calculation via parallelization. In the QM/MM re-refined donepezil structure, coordinate errors that previously existed in the PDB deposited geometry were improved leading to an improvement of the modeling of the interaction between donepezil and the aromatic side chains located in the AChE active site gorge. As a result of the re-refinement there was a 93% reduction in the donepezil conformational strain energy versus the original PDB structure. The results of the present effort offer further detailed structural and biochemical inhibitor-AChE information for the continued development of more effective and palliative treatments of Alzheimer disease.
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影响因子：
5.5
作者：
Fu, Zheng;Li, Xue;Merz, Kenneth M., Jr.
通讯作者：
Merz, Kenneth M., Jr.
影响因子：
5
作者：
Liston, DR;Nielsen, JA;White, WF
通讯作者：
White, WF
DOI：
10.1107/s0907444998003254
发表时间：
1998-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Brunger, AT;Adams, PD;Warren, GL
通讯作者：
Warren, GL
影响因子：
6.3
作者：
Alexeev, Y;Kendall, RA;Gordon, MS
通讯作者：
Gordon, MS
影响因子：
2.5
作者：
Davidsson, P;Blennow, K;Hesse, C
通讯作者：
Hesse, C