<em>In Silico</em> Identification of Potent Pancreatic Triacylglycerol Lipase Inhibitors from Traditional Chinese Medicine

<div><p>Pancreatic triacylglycerol lipase (PNLIP) are primary lipases that are critical for triacylglyceride digestion in human. Since reduced metabolism of triacylglyceride might be a plausible concept for weight loss, we screened for potential PNLIP inhibitors from traditional Chinese medicine (TCM) with the aim to identify weight loss candidate compounds. TCM candidates Aurantiamide, Cnidiadin, and 2-hexadecenoic acid exhibited higher Dock Scores than the commercial drug Orlistat, and were also predicted to have inhibitory characteristics against PNLIP using constructed MLR (R² = 0.8664) and SVM (R² = 0.9030) models. Molecular dynamics indicated that the TCM-PNLIP complexes formed were stable. We identified that the PNLIP binding site has several residues that can serve as anchors, and a hydrophobic corridor that provides additional stability to the complex. Aurantiamide, Cnidiadin, and 2-hexadecenoic acid all have features that correspond to these binding site features, indicating their potential as candidates for PNLIP inhibitors. The information presented in this study may provide helpful insights to designing novel weight-control drugs.</p> </div

Ligplot diagrams illustrating protein-ligand interactions.

<p>(A) Aurantiamide, (B) Cnidiadin, (C) 2-Hexadecenoic acid, (D) Orlistat.</p

Feature summary of the PNLIP binding site and TCM residues.

<p>(A) PNLIP binding site consists of two parallel hydrophobic regions and several residues for pi-interactions as depicted by the violet rings. Amino acid legends are colored according to hydropathy. (B–D) Ligand features of (B) Aurantiamide, (C) Cnidiadin, and (D) 2-Hexadecenoic acid in coordination to binding site features are shown. Amino acids residues and ligand moieties forming hydrophobic contacts are shown in pink. Residues are moieties involved in pi-interaction are shown in violet. H-bonds are illustrated by yellow dashed lines.</p

Mean smallest residue distances for individual residues using 40 ns MD conformations.

<p>Residues located in the active site cleft are shown in brackets within the enlarged illustration. (A) Aurantiamide, (B) Cnidiadin, (C) 2-Hexadecenoic acid, (D) Orlistat.</p

Adsorption model of the candidate compounds.

<p>Adsorption model of the candidate compounds.</p

Top and side views of test compounds within the binding site following MD simulation.

<p>(A) Aurantiamide, (B) Cnidiadin, (C) 2-Hexadecenoic acid, (D) Orlistat. (D) Orlistat. Residues involved in protein-ligand interactions are shown with pink surfaces, ligands are shown in yellow.</p

Torsion angle changes during 40 ns MD simulation.

<p>Each torsion angle is specified by a numerical and corresponds to the radar chart with the identical number. (A) Aurantiamide, (B) Cnidiadin, (C) 2-Hexadecenoic acid, (D) Orlistat.</p

Distance of H-bonds formed between test compounds and PNLIP binding site during MD.

<p>(A) Aurantiamide, (B) Cnidiadin, (C) 2-hexadecenoic acid, and, (D) Orlistat.</p

Secondary structure changes observed for binding cleft amino acid residues during the 40 ns MD simulation.

<p>(A) Aurantiamide, (B) Cnidiadin, (C) 2-Hexadecenoic acid, (D) Orlistat.</p

H-bond interactions between PNLIP and top three candidates and Orlistat.

<p>H-bond occupancy cutoff: 2.5 Å.</p