Exploring Aurone Derivatives as Potential Human Pancreatic Lipase Inhibitors through Molecular Docking and Molecular Dynamics Simulations

Abstract

Inhibition of human pancreatic lipase, a crucial enzyme in dietary fat digestion and absorption, is a potent therapeutic approach for obesity treatment. In this study, human pancreatic lipase inhibitory activity of aurone derivatives was explored by molecular modeling approaches. The target protein was human pancreatic lipase (PDB ID: 1LPB). The 3D structures of 82 published bioactive aurone derivatives were docked successfully into the protein catalytic active site, using AutoDock Vina 1.5.7.rc1. Of them, 62 compounds interacted with the key residues of catalytic trial Ser152-Asp176-His263. The top hit compound (A14), with a docking score of −10.6 kcal⋅mol−1, was subsequently submitted to molecular dynamics simulations, using GROMACS 2018.01. Molecular dynamics simulation results showed that A14 formed a stable complex with 1LPB protein via hydrogen bonds with important residues in regulating enzyme activity (Ser152 and Phe77). Compound A14 showed high potency for further studies, such as the synthesis, in vitro and in vivo tests for pancreatic lipase inhibitory activity.

2-Benzylidenebenzofuran-3(2H)-ones as a new class of alkaline phosphatase inhibitors: synthesis, SAR analysis, enzyme inhibitory kinetics and computational studies

“…52 As a member of the avonoid family, thus far aurones have been reported to possess different bioactivities including antitumor, anticancer, antioxidant, metal ion-chelating, antityrosinase, antiparasitic, antimicrobial, antiviral, anti-inammatory, anti-diabetic, anti-hormonal and anti-obesity activity. 53 They have been found to act as inhibitors for several enzymes such as monoamine oxidase A and B, histone deacetylase and cyclin-dependent kinase, 54 and thus represent an overwhelming and rapidly developing eld in modern heterocyclic chemistry. 55 Considering the literature ndings and in continuation of our previous studies 47,48 aimed at developing new molecules as potent biological candidates, herein, we report the design and synthesis of a new series of chalcones and aurones.…”

Antiobesity drug-likeness properties and pancreatic lipase inhibition of a novel low molecular weight lutein oxidized product, LOP6

“…21 In a study, aurone derivatives inhibited pancreatic lipase by blocking the protein active catalytic site especially interacting with the key residues of the catalytic triad Ser152-Asp176-His263. 60 In our study, the interaction of LOP6 with lipase did not bind directly to the key residues, since LOP6 showed mixed inhibition and was found to interact at the allosteric site instead of the catalytic site. Hence, LOP6 interacted with hydrogen bond residues such as TRP83, ARG265 and LYS239.…”

Discovery of Novel Epoxyketone Peptides as Lipase Inhibitors

“…The mechanism of orlistat inhibition against lipase enzyme is irreversible due to a covalent bond that results from the nucleophilic attack of the hydroxyl group side chain of serine 152 on the orlistat lactone ring [ 22 , 23 ]. However, the physical access via “protein binding” of the candidate inhibitor to the active site of the enzyme is essential to introduce the inhibitor in the vicinity of the serine residue in the active site.…”

“…The synthesized compounds depicted docking scores at least twice that of orlistat. Notably, it has been reported previously that low values of docking scores for orlistat do not correlate well with its potency against lipase enzymes [ 22 , 23 ]. This might be explained by the excessive conformational flexibility of orlistat alkyl chains which reduces its affinity to bind within the lipase active site or overpopulates the conformer library and masks the most active conformer(s).…”