Structure-based alignment and comparative molecular field analysis of acetylcholinesterase inhibitors
Structure-based alignment and comparative molecular field analysis of acetylcholinesterase inhibitors
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DOI：
10.1021/jm950771r
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发表时间：
1996-12-20
影响因子：
7.3
通讯作者：
Tropsha, A
中科院分区：
文献类型：
--
作者：
Cho, SJ;Garsia, MLS;Tropsha, A
采用比较分子场分析 (CoMFA) 方法来建立毒扁豆碱、9-氨基-1,2,3,4-四氢吖啶 (THA)、依酚铵 (EDR) 和其他结构多样的乙酰胆碱酯酶 (AChE) 抑制剂的定量构效关系。酶/抑制剂复合物晶体结构的可用性（EDR/AChE、THA/AChE 和十甲铵 (DCM)/AChE）（Harel, M.；等人，Quaternaryligand bond toaromatic residles in the active-site gorge of acetalcholinesterase. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 9031-9035）不仅提供了有关抑制剂活性构象的信息，还提供了有关抑制剂在酶活性位点中的相对相互方向的信息。 EDR 和 THA 的晶体构象用作模板，在其上叠加其他抑制剂。应用本实验室最近开发的交叉验证 R(2) 引导区域选择方法（Cho, S. J.；Tropsha, A. 比较分子场分析 (CoMFA) 的交叉验证 R(2) 引导区域选择：实现一致结果的简单方法。J. Med. Chem. 1995, 38, 1060-1066）对 60 种 AChE 抑制剂进行了高度预测的 CoMFA 模型q(2) 为 0.734。
The method of comparative molecular field analysis (CoMFA) was used to develop quantitative structure-activity relationships for physostigmine, 9-amino-1,2,3,4-tetrahydroacridine (THA), edrophonium (EDR), and other structurally diverse inhibitors of acetylcholinesterase (AChE). The availability of the crystal structures of enzyme/inhibitor complexes (EDR/AChE, THA/ AChE, and decamethonium (DCM)/AChE) (Harel, M.; et al. Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 9031-9035) provided information regarding not only the active conformation of the inhibitors but also the relative mutual orientation of the inhibitors in the active site of the enzyme. Crystallographic conformations of EDR and THA were used as templates onto which additional inhibitors were superimposed. The application of cross-validated R(2) guided region selection method, recently developed in this laboratory (Cho, S. J.; Tropsha, A. Cross-Validated R(2) Guided Region Selection for Comparative Molecular Field Analysis (CoMFA): A Simple Method to Achieve Consistent Results. J. Med. Chem. 1995, 38, 1060-1066), to 60 AChE inhibitors led to a highly predictive CoMFA model with the q(2) of 0.734.