In silico strategy for detailing the binding modes of a novel family of peptides proven as ghrelin receptor agonists
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ORIGINAL PAPER
In silico strategy for detailing the binding modes of a novel family of peptides proven as ghrelin receptor agonists Ania de la Nuez Veulens 1 & Rolando E. Rodríguez Fernández 2 & Yoanna M. Álvarez Ginarte 3 & Luis A. Montero Cabrera 3,4 Received: 24 June 2020 / Accepted: 17 September 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
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. Keywords GHS-R1a . Growth hormone secretagogue peptides . GPCR . Molecular dynamics . Ghrelin . Cyclic peptide
Abbreviations GPCR G protein coupled receptor GH Growth hormone GHS Growth hormone secretagogue GHS-R Growth hormone secretagogue receptor GHS-R1a Growth hormone secretagogue receptor 1a, also known as ghrelin receptor, the full active receptor that mediates biological actions
* Luis A. Montero Cabrera [email protected] 1
Department of Biochemistry, Faculty of Biology, University of Havana, Havana, Cuba
2
DNAdigest Ltd., Cambridge, UK
3
Laboratory of Theoretical and Computational Chemistry, Faculty of Chemistry, University of Havana, Havana, Cuba
4
Department of Chemistry, Johns Hopkins University, Baltimore, MD, USA
GHRP GOAT POPC RMSF RMSD NMR NPT PDB
of ghrelin and growth hormone secretagogues Growth hormone-releasing peptide Ghrelin-o-acyltransferase 1-Palmitoyl-2-oleoylsn-glycero-3-phosphocholine Root-mean-square fluctuation Root mean-square deviation; Nuclear magnetic resonance Constan
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