Structure Activity Relationship Studies on Novel Acylpiperidine Compounds Based on Insect OBP1

doi:10.7503/cjcu20130656

Abstract

Abstract:

The binding mode between 29 novel acylpiperidine compounds and odorant binding protein AgamOBP1 were studied with Sybyl7.3 software. The results show that the hydrophobic effect and the water-bridge interaction both mainly contribute to their binding affinity. Some terminated hydrophobic groups of these acylpiperidine compounds are indicated to be embed a hydrophobic, long and narrow tunnel in the binding pocket of AgamOBP1. Their acyl O forms multiple hydrogen bonds with some key residues Trp114 and Gly92 or Cys95 of AgamOBP1 via a water-bridge interaction with HOH153. The comparative molecular field analysis(CoMFA) and comparative molecular similarity indices analysis(CoMSIA) were used to build the 3D-quantitative structure-activity relationship(QSAR) models of acylpiperidine compounds. Cross-validation coefficients(r_cv²) of the obtained CoMFA and CoMSIA models are 0.650 and 0.587, respectively. In the best CoMSIA model, the hydrophobic, electrostatic and steric field effects are found to be important factors for the repellent activities of these acylpiperidine compounds, especially the hydrophobic effect. The structure-activity relationship of acylpiperidine compounds is revealed based on the binding pocket feature of AgamOBP1 and their 3D-QSAR models. These acylpiperidine compounds with a 9 or 10 carbon chain are indicated to be the best one in the repellent ability when the substituent group in their piperidine ring is identical in the size and position. The introduction of a bulky substituent group in the piperidine ring is shown to be unfavorable to the repellent activities of these acylpiperidine compounds with the same long hydrophobic carbon chain because of the size limitation of the AgamOBP1 binding pocket. The acyl group of these acylpiperidine compounds as a hydrogen donor group is proposed to be necessary for recognizing and binding to AgamOBP1. These studies will provide a theoretical foundation for the bio-rational design of novel acylpiperidine repellent molecules.

Key words: Odorant binding protein, Acylpiperidine compound, Insect repellent, Molecular docking, 3D quantitative structure-activity relationship

CLC Number:

O641

TrendMD:

CHEN Wen-Ya, WANG Shan-Shan, LI Dong-Ling, PENG Wei, ZHAO Jing-Fu, DUAN Hong-Xia. Structure Activity Relationship Studies on Novel Acylpiperidine Compounds Based on Insect OBP1[J]. Chem. J. Chinese Universities, 2013, 34(12): 2798.

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