Prediction and evaluation of the lipase inhibitory activities of tea polyphenols with 3D-QSAR models.
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, R4and R5, hydrophilic substituents in R1and electron withdrawing groups in R2are 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.
Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China.|Anti-stress Health Research Center, College of Pharmacy, Jinan University, Guangzhou 510632, China.
Yi-Fang
YF
Li
Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China.
Yi-Qun
YQ
Chang
Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China.|Anti-stress Health Research Center, College of Pharmacy, Jinan University, Guangzhou 510632, China.
Jie
J
Deng
Anti-stress Health Research Center, College of Pharmacy, Jinan University, Guangzhou 510632, China.|Yunnan University of Traditional Chinese Medicine, Kunming 650500, China.
Wei-Xi
WX
Li
Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China.
Jie
J
Jian
Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China.
Jia-Suo
JS
Gao
Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China.|Anti-stress Health Research Center, College of Pharmacy, Jinan University, Guangzhou 510632, China.
Xin
X
Wan
Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China.
Hao
H
Gao
Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China.|Anti-stress Health Research Center, College of Pharmacy, Jinan University, Guangzhou 510632, China.
Hiroshi
H
Kurihara
Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China.
Ping-Hua
PH
Sun
Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China.|Anti-stress Health Research Center, College of Pharmacy, Jinan University, Guangzhou 510632, China.
Rong-Rong
RR
He
D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D008049:Lipase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008297:Male; D062105:Molecular Docking Simulation; D010179:Pancreas / Q000201:enzymology*; D059808:Polyphenols / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013662:Tea / Q000737:chemistry*
D004791:Enzyme Inhibitors; D059808:Polyphenols; D013662:Tea; D008049:Lipase
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