GHRP-6
Growth Hormone Releasing Peptide-6, Growth hormone-releasing hexapeptide, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2
In silico strategy for detailing the binding modes of a novel family of peptides proven as ghrelin receptor agonists.
de la Nuez Veulens. Ania A; Rodríguez Fernández. Rolando E RE; Álvarez Ginarte. Yoanna M YM; Montero Cabrera. Luis A LA
Key Findings
- The novel cyclic peptides A228 and A233 bind the ghrelin receptor (GHS‑R1a) in the same overall orientation as ghrelin and GHRP‑6.
- Binding relies on the peptide’s N‑terminal interacting with residue E124 and an aromatic residue that contacts an aromatic cluster (F279, F309, F312) in the receptor.
- A basic pharmacophore was proposed: a positively charged amine and an aromatic ring spaced about 0.79 nm apart.
Practical Outcomes
- For DIY biohackers, the study highlights structural features (positive charge + aromatic ring) that are important for ghrelin‑receptor activation, which could guide the selection or design of new analogs. However, it provides no dosage, safety, or in‑vivo efficacy data, so it’s not directly usable for self‑experimentation but may inform future peptide development.
Summary
Scientists used computer models to see how two new cyclic peptides (A228 and A233) stick to the ghrelin receptor, comparing them to the natural hormone ghrelin and the known peptide GHRP‑6. They found the new peptides bind in a similar way, mainly using a positively charged start (N‑terminal) and an aromatic side‑chain that lines up with a specific pocket on the receptor. From this they suggested a simple design rule (pharmacophore) for making effective ghrelin‑like compounds.
Abstract
Ghrelin is a peptide hormone involved in multiple functions, including growth hormone release stimulation, food intake regulation, and metabolic and cytoprotective effect. A novel family of peptides with internal cycles was designed as ghrelin analogs and the biological activity of two of them (A228 and A233) was experimentally studied in-depth. In this work, an in silico strategy was developed for describing and assessing the binding modes of A228 and A233 to GHS-R1a (ghrelin receptor) comparing it with ghrelin and GHRP-6 peptides. Several reported structures of different G protein coupled receptors were used as templates, to obtain a good quality model of GHS-R1a. The best model was selected by preliminary molecular docking with ghrelin and GHRP-6. Docking was used to estimate peptide orientations in the binding site of the best model, observing a superposition of its N-terminal and its first aromatic residue. To test the complex stability in time, the C-terminal fragments of each peptide were added and the complexes were inserted a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) membrane, performing a molecular dynamic simulation for 100 ns using the CHARMM36 force field. Despite of the structural differences, the studied peptides share a common binding mode; the N-terminal interacts with E124 and the aromatic residue close to it, with the aromatic cluster (F279, F309, and F312). A preliminary pharmacophore model, consisting in a positive charged amine and an aromatic ring at an approximate distance of 0.79 nm, can be proposed. The results here described could represent a step forward in the efficient search of new ghrelin analogs.
Study Information
pubmed
2020
2020-10-05T00:00:00.000Z
10.1007/s00894-020-04553-8
2
74