Prediction and evaluation of the lipase inhibitory activities of tea polyphenols with 3D-QSAR models.

Yi-Fang Li,Yi-Qun Chang,Ping-Hua Sun,Jia-Suo Gao,Jie Jian,Hao Gao,Wei-Xi Li,Hiroshi Kurihara,Jie Deng,Xin Wan,Rong-Rong He

doi:10.1038/srep34387

Abstract

The extraordinary hypolipidemic effects of polyphenolic compounds from tea have been confirmed in our previous study. To gain compounds with more potent activities, using the conformations of the most active compound revealed by molecular docking, a 3D-QSAR pancreatic lipase inhibitor model with good predictive ability was established and validated by CoMFA and CoMISA methods. With good statistical significance in CoMFA (r2cv = 0.622, r2 = 0.956, F = 261.463, SEE = 0.096) and CoMISA (r2cv = 0.631, r2 = 0.932, F = 75.408, SEE = 0.212) model, we summarized the structure-activity relationship between polyphenolic compounds and pancreatic lipase inhibitory activities and find the bulky substituents in R2, R4 and R5, hydrophilic substituents in R1 and electron withdrawing groups in R2 are the key factors to enhance the lipase inhibitory activities. Under the guidance of the 3D-QSAR results, (2R,3R,2′R,3′R)-desgalloyloolongtheanin-3,3′-O-digallate (DOTD), a potent lipase inhibitor with an IC50 of 0.08 μg/ml, was obtained from EGCG oxidative polymerization catalyzed by crude polyphenol oxidase. Furthermore, DOTD was found to inhibit lipid absorption in olive oil-loaded rats, which was related with inhibiting the activities of lipase in the intestinal mucosa and contents.

Highlights

Established and validated by CoMFA and CoMISA methods to further understand the structure-activity relationship between polyphenolic compounds and pancreatic lipase inhibitory activities
The external validation is a vital part of the model verification and its r2pred values calculated based on both training and test set are respectively 0.918 and 0.773 for CoMFA and CoMSIA model (Table 2)
When DOTD (100 mg/kg) was administrated to rats, the lipase activities were significantly inhibited. These results indicated DOTD with potent lipase inhibitory effect in vivo

Summary

Introduction

Established and validated by CoMFA and CoMISA methods to further understand the structure-activity relationship between polyphenolic compounds and pancreatic lipase inhibitory activities. The external validation is a vital part of the model verification and its r2pred values calculated based on both training and test set are respectively 0.918 and 0.773 for CoMFA and CoMSIA model (Table 2). Cyan contour located near R2 indicates hydrogen bond donor induced here can increase the activity of compounds.

Results

Conclusion