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Structure-activity relationship of dietary flavonoids on pancreatic lipase.

ABSTRACT: Lipase is a very important digestive enzyme for triglyceride absorption in vivo. The inhibitory activities of 26 dietary flavonoids, including flavone, flavanone, isoflavone and flavanol, on lipase were determined. Flavone exhibited stronger inhibitory activity than other types of flavonoids. Among them, luteolin exhibited the strongest inhibitory activity with IC50 value of 99 ± 11 μM, followed by quercetin and baicalein. The binding affinity of these flavonoids with lipase was investigated by fluorescence titration method. The binding affinity of flavones was stronger than flavanones, and was linearly positively correlated with their inhibitory activity. The binding of flavones on lipase caused the blue-shift of fluorescence, while flavanones caused red-shift. The analysis of structure-activity relationship of flavonoids on lipase revealed that the structure of C ring is very crucial. The hydrogenation of C2=C3 bond and the absence of C=O group in C ring both caused significant decrease of inhibitory activity. Besides, the hydroxylation on ring A and B of flavones increased the activity, while glycosylation weakened the activity. Molecular docking analysis confirmed that C2=C3 bond in C ring of flavones increases the π-conjugation and contributes to maintaining the planarity of flavonoid structure, which favour its Pi-Pi interaction with lipase.

SUBMITTER: Li MM

PROVIDER: S-EPMC9813676 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Structure-activity relationship of dietary flavonoids on pancreatic lipase.

Li Mang-Mang MM Chen Yi-Ting YT Ruan Jin-Cang JC Wang Wen-Jun WJ Chen Ji-Guang JG Zhang Qing-Feng QF

Current research in food science 20221224

Lipase is a very important digestive enzyme for triglyceride absorption in vivo. The inhibitory activities of 26 dietary flavonoids, including flavone, flavanone, isoflavone and flavanol, on lipase were determined. Flavone exhibited stronger inhibitory activity than other types of flavonoids. Among them, luteolin exhibited the strongest inhibitory activity with IC50 value of 99 ± 11 μM, followed by quercetin and baicalein. The binding affinity of these flavonoids with lipase was investigated by ...[more]

PMID: 36618100

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Project description:Background/Objectives: Obesity has reached pandemic proportions, with predictions suggesting that, by 2030, over 1.5 billion people will be affected. Pancreatic lipase (PL), the enzyme primarily responsible for the absorption of dietary lipids, presents a potential target for obesity management. However, while porcine pancreatic lipase (PPL) is commonly used as the enzyme source for screening potential inhibitors, its effect on human pancreatic lipase (HPL) is rarely reported. This work aimed to screen the inhibitory effects of a library of flavonoids with different functional groups on the activity of PL from the human pancreas (triacylglycerol acyl hydrolase, EC 3.1.1.3) and compare it to the effects of the porcine pancreas (type II, EC 3.1.1.3), establishing, whenever possible, a structure-activity relationship. Methods: The inhibitory effects of a library of 48 flavonoids with different hydroxy, glycosyl, rutinosyl, galloyl, and extended alkyl groups were evaluated against PPL and HPL. The kinetic parameters and inhibitory mechanisms of the most active flavonoids were determined, and in silico docking studies of the more potent flavonoids were also performed, using the active site of HPL. Results/Conclusions: Variations in enzyme catalytic activity were observed depending on the source of the enzyme. The inhibitory effect was particularly influenced by the presence of extended alkyl groups at the C-3 of the C-ring and the C2=C3 double bond of the C-ring and the presence of a pyrogallol group at the C-2', C-3' and C-4' of the B-ring. Docking results showed a strong correlation between docking scores and observed inhibitory activities, highlighting the critical role of specific substituents on the flavonoid backbone in enhancing detailed interaction dynamics with key amino acids. Compounds 28, 29, and 30, with alkyl groups, showed the highest docking scores, interacting with residues HIS151, PHE215, ARG256, and HIS263. Further analysis also revealed that specific substituents improved pocket occupancy and formed additional interactions with residues TYR114, PRO180, ILE209, and PHE215, which are crucial for inhibition. These binding characteristics closely mimic those observed with orlistat, reinforcing their mechanistic similarities in inhibiting HPL and validating their inhibitory activities.

Project description:With the aim to establish a structure-inhibitory activity relationship of flavonoids against dipeptidyl peptidase-4 (DPP-4) and elucidate the interaction mechanisms between them, a pannel of 70 structurally diverse flavonoids was used to evaluate their inhibitory activities against DPP-4, among which myricetin, hyperoside, narcissoside, cyanidin 3-O-glucoside, and isoliquiritigenin showed higher inhibitory activities in a concentration-dependent manner. Structure-activity relationship analysis revealed that introducing hydroxyl groups to C3', C4', and C6 of the flavonoid structure was beneficial to improving the inhibitory efficacy against DPP-4, whereas the hydroxylation at position 3 of ring C in the flavonoid structure was unfavorable for the inhibition. Besides, the methylation of the hydroxyl groups at C3', C4', and C7 of the flavonoid structure tended to lower the inhibitory activity against DPP-4, and the 2,3-double bond and 4-carbonyl group on ring C of the flavonoid structure was essential for the inhibition. Glycosylation affected the inhibitory activity diversely, depending on the structure of flavonoid aglycone, type of glycoside, as well as the position of substitution. Inhibition kinetic analysis suggested that myricetin reversibly inhibited DPP-4 in a non-competitive mode, whereas hyperoside, narcissoside, cyanidin 3-O-glucoside, and isoliquiritigenin all reversibly inhibited DPP-4 in a mixed type. Moreover, the fluorescence quenching analysis indicated that all the five flavonoid compounds could effectively quench the intrinsic fluorescence of DPP-4 by spontaneously binding with it to form an unstable complex. Hydrogen bonds and van der Waals were the predominant forces to maintain the complex of myricetin with DPP-4, and electrostatic forces might play an important role in stabilizing the complexes of the remaining four flavonoids with DPP-4. The binding of the tested flavonoids to DPP-4 could also induce the conformation change of DPP-4 and thus led to inhibition on the enzyme. Molecular docking simulation further ascertained the binding interactions between DPP-4 and the selected five flavonoids, among which hyperoside, narcissoside, cyaniding 3-O-glucoside, and isoliquiritigenin inserted into the active site cavity of DPP-4 and interacted with the key amino acid residues of the active site, whereas the binding site of myricetin was located in a minor cavity close to the active pockets of DPP-4.

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Structure-activity relationship of dietary flavonoids on pancreatic lipase.

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Structure-activity relationship of dietary flavonoids on pancreatic lipase.

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