摘要
ＡｎａｌｙｓｉｓｏｆｅｌｅｃｔｒｏｎｉｃｓｔｒｕｃｔｕｒｅｓｏｆｐｈｙｓｏｓｔｉｇｍｉｎｅａｎａｌｏｇｓＨＵＺｅｎｇＪｉａｎ，ＪＩＡＮＧＨｕａＬｉａｎｇ，ＣＨＥＮＪｉａｎＺｈｏｎｇ，ＣＨＥＮＫａｉＸｉａｎ１，ＪＩＲｕＹｕｎ（Ｓｈａｎｇｈａｉ...
AIM: To elucidate the action mechanism and structural prerequisites of 21 physostigmine analogs as acetylcholinesterase inhibitors at the molecular level, and help the rational design of these dihydroindoline inhibitors. METHODS: Initial structures of these compounds were built and minimized by SYBYL 6 2 molecular modeling software. Conformations of those molecules with the highest predictive abilities in the Comparative Molecular Field Analysis model were chosen to the semiempirical quantum chemical calculations. RESULTS: (1) The highest occupied molecular orbital (HOMO) consisted mainly of the orbitals in phenyl group and N 1 atom; the lowest unoccupied molecular orbital (LUMO) of the molecules was contributed from phenyl group and C 11 atom. While the HOMO energies did not show any recognizable relationship with activity, the LUMO energies showed a decreased tendency with increasing activity. The active compounds showed lower LUMO energies. (2) The carbon atom (C 11 ) had the most positive net atom charge. The most active compound had the most positive charge on this carbon, but had the lower charges on the carbonyl oxygen (O 12 ) which was the most negative charge atom. (3) The bond order of carbon oxygen bond (C 11 -O 10 ) was invariant across the series of the compounds. (4) Compounds with too high or too low total dipole moment had lower activities, while the most active one had a lower molecular polarizability. CONCLUSION: A molecular model was suggested to explain the possible mode of action by which these compounds inhibit acetylcholinesterase.
出处
《中国药理学报》
CSCD
1998年第4期322-326,共5页
Acta Pharmacologica Sinica
关键词
胆碱酯酶抑制
毒扁豆碱
电子结构
分子模型
cholinesterase inhibitors
physostigmine
molecular models
computer aided design
