1. 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.
- Author
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Wong, Ann Rann, Hung, Andrew, Yang, Angela Wei Hong, Gill, Harsharn, and Lenon, George Binh
- Subjects
MOLECULAR dynamics ,URACIL derivatives ,REGULATION of body weight ,NEUROPEPTIDES ,ACETATES ,STRUCTURAL stability ,HERBAL medicine - 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 Y
1 receptor (Y1 R) remain largely unknown. This study aimed to screen PC compounds for favourable pharmacokinetics profiles and examine their molecular mechanisms targeting Y1 R. Forty-three PC compounds were systematically sought from pharmacological databases and docked with Y1 R (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 Y1 R 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 Y1 R in a closed position. Owing to their selective interaction with Phe302, an important residue in binding of selective Y1 R 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-Y1 R 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 Y1 R inhibitor. [ABSTRACT FROM AUTHOR]- Published
- 2023
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