Acta Phys. -Chim. Sin. ›› 2009, Vol. 25 ›› Issue (07): 1379-1384.doi: 10.3866/PKU.WHXB20090720

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Molecular Docking of the Acetylcholinesterase Inhibitor Corydaline and Virtual Screening of Open Ring Derivatives

JIANG Yu-Ren, XU Hui, CHEN Fang-Jun, MA Guan-Jun   

  1. College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, P. R. China
  • Received:2009-01-21 Revised:2009-03-19 Published:2009-06-26
  • Contact: JIANG Yu-Ren E-mail:jiangyr@mail.csu.edu.cn; xuhui0820@163.com

Abstract:

We used molecular docking software GOLD to investigate the binding mode of corydaline, a type of cordalis alkaloid, with acetylcholinesterase and to screen a series of open ring derivatives with different carbon linkages and different substituent groups. The best result was obtained when corydaline was bound to the enzyme catalytic site in an open conformation. The conformation model indicates that phenyl ring A interacts with the phenyl group of Tyr334 via a classic parallel π-π accumulation and that the positively charged nitrogen atom interacts with the phenyl group of Phe330 in the hydrophobic site by the cation-π effect. Both dimethoxy radicals of phenyl D that penetrate to the bottom of the active pocket interact at the catalytic position. Virtual screening showed that the scores of most derivatives were higher than that of corydaline and that the 15 open ring substances with the highest scores were mainly derived from those substituted by phenoxy groups and those with 2 to 7 carbon linkages. Based on these virtual screening results, compound 7 was synthesized and a pharmacological study showed that its inhibition activity was three times as high as galanthamine.

Key words: Corydaline, Acetylcholinesterase, Molecular docking, Open ring derivative, Virtual screening

MSC2000: 

  • O641