Rational Design, Discovery, and Synthesis of a Novel Series of Potent Growth Hormone Secretagogues

Abstract

In the joint experimental and computational efforts reported here to obtain novel chemical entities as growth hormone secretagogues (GHSs), a small database of peptides and non-peptides known to have GHS activity was used to generate and assess a 3D pharmacophore for this activity. This pharmacophore was obtained using a systematic and efficient procedure, "DistComp", developed in our laboratory. The 3D pharmacophore identified was then used to search 3D databases to explore chemical structures that could be novel GHSs. A number of these were chosen for synthesis and assessment of their ability to release growth hormone (GH) from rat pituitary cells. Among the compounds tested, those with a benzothiazepin scaffold were discovered with micromolar activity. To facilitate lead optimization, a second program, a site-dependent fragment QSAR procedure was developed. This program calculates a library of chemical and physical properties of "fragments" or chemical components in a known pharmacophore and determines which, if any, of these properties are important for the observed activity. The combined use of the 3D pharmacophore and the results of the site-dependent fragment QSAR analysis led to the discovery and synthesis of a novel series of potent GHSs, a number of which had nanomolar in vitro activity.

Ghrelin Receptor Modulators and Their Therapeutic Potential

“…New GH secretagogues were obtained by computational procedures, using two GHS agonists as templates [114], or by a generation of a 3D pharmacophore, that allowed a screening of a 3D database [115]. No in vivo assays have been conducted for the compounds thus identified.…”

Recent Developments in Ghrelin Receptor Ligands

“…[90] Researchers at Kaken Pharmaceutical identified a new series of GHSs by using a virtual screening method. [126] For this purpose they developed a three-dimensional model of the GHS pharmacophore by molecular modeling based on structurally different GHSs (peptidyl and nonpeptidyl). This study led to the identification of several hits, such as compound 39 (Figure 17), which presents a modest in vitro stimulating activity.…”

Emerging Drugs - Potential for Misuse in Sport and Doping Control Detection Strategies

“…Based on molecular modeling and computational design strategies using peptidyl and non-peptidyl model compounds, six pharmacophoric sites were assigned to GHRP-6 [64]. Most of these sites, which include two aromatic ring structures, a proton acceptor residue (e.g.…”