Poria cocos compounds targeting neuropeptide Y1 receptor (Y1R) for weight management: A computational ligand- and structure-based study with molecular dynamics simulations identified beta-amyrin acetate as a putative Y1R inhibitor

Ann Rann Wong; Andrew Hung; Angela Wei Hong Yang; Harsharn Gill; George Binh Lenon

doi:10.1371/journal.pone.0277873

Poria cocos compounds targeting neuropeptide Y1 receptor (Y1R) for weight management: A computational ligand- and structure-based study with molecular dynamics simulations identified beta-amyrin acetate as a putative Y1R inhibitor

PLoS One. 2023 Jun 30;18(6):e0277873. doi: 10.1371/journal.pone.0277873. eCollection 2023.

Authors

Ann Rann Wong¹, Andrew Hung², Angela Wei Hong Yang¹, Harsharn Gill², George Binh Lenon¹

Affiliations

¹ School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia.
² School of Science, RMIT University, Melbourne, Victoria, Australia.

Abstract

Poria cocos (PC) is a medicinal herb frequently used in weight-loss clinical trials, however the mechanisms by which its compounds target orexigenic receptors including the neuropeptide Y1 receptor (Y1R) remain largely unknown. This study aimed to screen PC compounds for favourable pharmacokinetics profiles and examine their molecular mechanisms targeting Y1R. Forty-three PC compounds were systematically sought from pharmacological databases and docked with Y1R (PDB: 5ZBQ). By comparing the relative binding affinities, pharmacokinetics and toxicity profiles, we hypothesised that compounds designated PC1 3,4-Dihydroxybenzoic acid, PC8 Vanillic acid, PC40 1-(alpha-L-Ribofuranosyl)uracil, could be potential antagonists as they contact major residues Asn283 and Asp287, similar to various potent Y1R antagonists. In addition, PC21 Poricoic acid B, PC22 Poricoic acid G and PC43 16alpha,25-Dihydroxy-24-methylene-3,4-secolanosta-4(28),7,9(11)-triene-3,21-dioic acid, contacting Asn299, Asp104 and Asp200 proximal to the extracellular surface could also interfere with agonist binding by stabilising the extracellular loop (ECL) 2 of Y1R in a closed position. Owing to their selective interaction with Phe302, an important residue in binding of selective Y1R antagonists, PC12 beta-Amyrin acetate, PC26 3-Epidehydrotumulosic acid and PC27 Cerevisterol were proposed as putative antagonists. Following the consensus approach, PC12 beta-Amyrin acetate, PC26 3-Epidehydrotumulosic acid and PC27 Cerevisterol were identified as candidate compounds due to their high affinities (-12.2, -11.0 and -10.8 kcal, respectively), high drug-likeness and low toxicity profiles. Trajectory analyses and energy contributions of PC12-Y1R complex further confirmed their structural stability and favourable binding free energies, highlighting the feasibility and possible development of PC12 beta-Amyrin acetate as a future Y1R inhibitor.

Copyright: © 2023 Wong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Ligands
Molecular Dynamics Simulation
Neuropeptides*
Wolfiporia*

Substances

beta-amyrin acetate
Ligands
dihydroxycarbene
Neuropeptides

Grants and funding

We thank the National Computing Infrastructure (NCI), which is supported by the Australian Government, for providing resources and services to assist with computational work in this study. Molecular dynamics simulations were undertaken using the LIEF HPC-GPGPU facility hosted at the University of Melbourne. This Facility was established with the assistance of LIEF Grant LE170100200. AW acknowledges financial support through the Australian Government Research Training Program (RTP) Scholarship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.