In Silico Identification of Potent PPAR‐γ Agonists from Traditional Chinese Medicine: A Bioactivity Prediction, Virtual Screening, and Molecular Dynamics Study

Abstract

The peroxisome proliferator-activated receptors (PPARs) related to regulation of lipid metabolism, inflammation, cell proliferation, differentiation, and glucose homeostasis by controlling the related ligand-dependent transcription of networks of genes. They are used to be served as therapeutic targets against metabolic disorder, such as obesity, dyslipidemia, and diabetes; especially, PPAR-γ is the most extensively investigated isoform for the treatment of dyslipidemic type 2 diabetes. In this study, we filter compounds of traditional Chinese medicine (TCM) using bioactivities predicted by three distinct prediction models before the virtual screening. For the top candidates, the molecular dynamics (MD) simulations were also utilized to investigate the stability of interactions between ligand and PPAR-γ protein. The top two TCM candidates, 5-hydroxy-L-tryptophan and abrine, have an indole ring and carboxyl group to form the H-bonds with the key residues of PPAR-γ protein, such as residues Ser289 and Lys367. The secondary amine group of abrine also stabilized an H-bond with residue Ser289. From the figures of root mean square fluctuations (RMSFs), the key residues were stabilized in protein complexes with 5-Hydroxy-L-tryptophan and abrine as control. Hence, we propose 5-hydroxy-L-tryptophan and abrine as potential lead compounds for further study in drug development process with the PPAR-γ protein.

Beware of docking!

“…For example, in Table 2 the control compound (T2384) has a very high dock score (77.615) and thus has a very high predictive activity from the different ligand-based methods, including multiple linear regression (MLR) [45], support vector machine (SVM) [46], and Bayesian network toolbox (BNT) [47]. However, the other compounds also have a very high predicted activity but a very low dock score [48]. From Table 2, the docking results show that the control compound (D71904) with the lowest binding energy has a low predicted activity from the ligand-based prediction (MLR and SVM).…”

Molecular Dynamics Free Energy Simulation study to Investigate Binding Pattern of Isoliquiritigenin as PPAR𝛾 Agonist

“…Similar binding mode was observed in molecular docking results [42] . The pi interactions with Phe 264, Phe 363 and h bond with Leu 340, Tyr 473. in silico identi cation of PPAR γ agonist from Chinese medicine showed similar interactions as H bond with residue Tyr 327, Lys 367 etc [50] . Quantitative parameters such as RMSD showed structural stability of the protein ligand complex.…”

The peroxisome proliferator‐activated receptors in cardiovascular diseases: experimental benefits and clinical challenges

“…Screening the TCM database containing more than 30 000 candidates, two TCM compounds, (S)‐tryptophan‐betaxanthin and berberrubine, have been identified as potential lead compounds targeting more than one PPAR (Chen et al ., ). By in silico identification, two other TCM candidates, 5‐hydroxy‐L‐tryptophan and abrine, were found to bind to PPARγ (Chen and Chen, ). In addition, honokiol from TCM Magnolia bark was also in silico predicted to bind to the ligand‐binding domain of PPARγ and prevent ed hyperglycaemia in diabetic mice (Atanasov et al ., ).…”