Natural Isoflavones and Semisynthetic Derivatives as Pancreatic Lipase Inhibitors

Abstract

Obesity, now widespread all over the world, is frequently associated with some chronic diseases. Thus, there is a growing interest in the prevention and treatment of obesity. To date, the only antiobesity drug is orlistat, a natural product-derived pancreatic lipase (PL) inhibitor with some undesired side effects. In the last decades, many natural compounds or derivatives have been evaluated as potential PL inhibitors, and natural polyphenols are among the most promising for possible exploitation as antiobesity agents. However, few studies have been devoted to isoflavones. In this work, we report a study on the PL inhibitory properties of a small library of semisynthetic isoflavone derivatives together with the natural leads daidzein (1), genistein (2), and formononetin (3). In vitro lipase inhibition assay showed that 2 is the most promising PL inhibitor. Among synthetic isoflavones, the hydroxylated and brominated derivatives were more potent than their natural leads. Detailed studies through fluorescence measurements and kinetics of lipase inhibition showed that 2 and the bromoderivatives 10 and 11 have the greatest affinity for PL. Docking studies corroborated these findings highlighting the interactions between isoflavones and the enzyme, confirming that hydroxylation and bromination are useful modifications.

Efficient screening of pancreatic lipase inhibitors from cod meat hydrolysate through ligand fishing strategy

“…The IC 50 value of GSPPPSG for PL was 0.60 mg/mL, and the IC 50 value of KLEGDLK was 1.08 mg/mL, which were 5.5 and 3.1 times higher than the initial CMH activity (IC 50 = 3.33 mg/mL), respectively. The activity of these two peptides was about one-third that of orlistat (positive drug, IC 50 of 14.6 μg/mL), which was also similar to the reported activities of natural products and synthetic compounds ( 17 , 28 , 29 ).…”

“…In other words, it competes with the substrate for binding PL and can also bind to the PL-substrate complex. The value of the competitive inhibition constant K i (4.19 mM) was higher than the non-competitive inhibition constant K' i (1.46 mM) ( Table 1 ), suggesting that GSPPPSG could bind tightly to the PL-substrate complex ( 29 ). Interestingly, KLEGDLK is a competitive PL inhibitor, as judged by an increase in K m value and a constant V m value ( Figure 5D ; Table 1 ).…”

“…The active site of PL (1LPB) is composed of the catalytic triad Ser 152-Asp 176-His 263. This catalytic site is highly restricted by a hydrophobic lid domain consisting of amino acids Gly 76-Lys 80, Leu 213-Met 217 ( 17 , 29 , 35 ). From the above analysis, it can be seen that both peptides can interact with Ser 152 and His 263 of the catalytic center.…”

“…According to the method reported in the previous literature, with a slight modification, the type of inhibition of PL by active peptides was determined ( 29 , 30 ). The peptide (0.8 mg/mL, final concentration) was reacted with different concentrations (0, 5, 10, 15, 20 mg/mL) of PL for 10 min, then 10 mM p NPB was added for 10 min.…”

Molecular structures, chemical descriptors and pancreatic lipase (1LPB) inhibition by natural products: A DFT investigation and molecular docking prediction

“…Indeed, several works attempted to predict the inhibition of the human pancreatic lipase (PDB ID: 1LP) by means of natural products and related compounds using the molecular docking techniques [13][14][15][16].…”