Discovery of Small Molecule Agonist of Gonadotropin-Releasing Hormone Receptor (GnRH1R)

Abstract

The gonadotrophin-releasing hormone (GnRH) is a central regulator of the human reproductive system and exerts physiological effects by binding to GnRH1R. The GnRH–GnRH1R system is a promising therapeutic target for the maintenance of reproductive function. There are several GnRH1R agonists on the market, but like GnRH, they are all peptide compounds and are limited by their way of administration (subcutaneous or intramuscular injection). To date, no published GnRH1R small molecule agonists have been reported. In this paper, the HTRF-based screening method has been used to screen our in-house chemical library, and we found and confirmed CD304 as a hit compound. Subsequently, structure optimization led to the discovery of compound 6d, exhibited with a certain GnRH1R activation activity (EC50: 1.59 ± 0.38 μM). Further molecular dynamics simulation experiments showed that 6d can well bind to the orthosteric site of GnRH1R through forming a hydrogen-bonding interaction with Y2836.51. Binding of 6d further induces conformational changes in TM6 and TM7, promoting the formation of a continuous water channel in GnRH1R, thereby promoting GnRH1R activation. This well-characterized hit compound will facilitate the further development of novel small molecule agonists of GnRH1R.

Peptide-Drug Conjugates: Design, Chemistry, and Drug Delivery System as a Novel Cancer Theranostic

“…The second is a low-affinity site for high-capacity receptors−which is identical with GnRH-1R found in human corpus luteum and placenta (X 7 -X 8 -Pro-Gly; tetrapeptide which interacts only with high GnRH concentrations) as presented in Figure 6b. 120 Interestingly, GnRH-2R was not found to be functional in normal reproductive organs in humans; however, high expression was observed in the cancerous tissues of the same organs. 121 GnRH agonists and antagonists were observed to possess efficient dose-/ time-dependent antiproliferation activities against human cancer cell lines as well as increasing expressions of GnRH significantly results in the downregulation of BCL-2 and up-regulation of C-MYC, BAX, and caspase-3/-9 enzymes, which ultimately induces apoptosis in cancer cells.…”

“…(b) 2D schematic representation of GnRH peptides having two-active sites for receptor binding. (c) 2D sequences of GnRH agonists and their analogs approved for targeting GnRH-1R, adopted with permission from references cited . (d) Further, various GnRH (or LHRH)-drug conjugates possess significant therapeutic potentials.…”

“…There are two-active sites in GnRH peptides responsible for binding with cancer cells; one is a high-affinity site for low-capacity receptorswhich are identical with GnRH-1R located in pituitary GnCs (Glu-His-Trp; tripeptide which fully interacts with low concentration GnRH). The second is a low-affinity site for high-capacity receptors–which is identical with GnRH-1R found in human corpus luteum and placenta (X 7 -X 8 -Pro-Gly; tetrapeptide which interacts only with high GnRH concentrations) as presented in Figure b …”

“…Additionally, crizotinib (anaplastic lymphoma kinase (ALK) inhibitor was also conjugated with [ d -Lys6]-GnRH-I targeting peptide to study the GnRH-receptor mediated internalization into nonsmall cell lungs cancer (NSCLC) tissues to exert potent c-Met kinase inhibitory effect . Other famous examples of PDCs consist of GnRH agonists conjugated with chemotherapeutic drugs via covalent linkage are shown in Figure d. , …”

Discovery of 4-(1,2,4-Oxadiazol-5-yl)azepan-2-one Derivatives as a New Class of Cannabinoid Type 2 Receptor Agonists for the Treatment of Inflammatory Pain

“…Molecular Dynamics Simulations. Similar to our previous study, 66 in this study, the binding model of the ligand was explored by means of molecular dynamics (MD) simulations in this study. The initial receptor−ligand complex structure was obtained from the molecular docking study.…”