Characteristics of Parathyroid hormone-1 Receptor Agonists and Antagonists

Abstract

Aim: Parathyroid hormone-1 receptor (PTH1R) is a member of B G protein-coupled receptors. The agonistic activation of the PTH1R results in the production and secretion of osteoclast-stimulating cytokines while antagonists may be used to treat bone metastases, hypercalcemia, cachexia and hyperparathyroidism. Results: We built pharmacophore models and investigated the characteristics of PTH1R agonists and antagonists. The agonist model consists of three hydrophobic points, one hydrogen bond acceptor and one positive ionizable point. The antagonist model consists of one hydrogen bond donor and three hydrophobic points. Conclusion: The features of the two models are similar, but the hydrogen bond acceptor, which is the main difference between PTH1R agonists and antagonists, suggests it may be essential for the agonist.

Mind the Gap—Deciphering GPCR Pharmacology Using 3D Pharmacophores and Artificial Intelligence

“…CPU03 showed much greater affinity to PTHR1 than CPU01, which was attributed to the fact that CPU03 fulfilled the agonist-based 3D pharmacophore model features to a greater extent than CPU01 was able to fulfill the antagonist-based model. Thus, these findings demonstrate the ability of 3D pharmacophore modeling to rationalize SARs by defining characteristics of PTHR1 agonists and antagonists [101].…”

“…Zhong and coworkers [101] generated a representative 3D pharmacophore agonist model from a set of parathyroid hormone-1 receptor (PTHR1) agonists, and a representative antagonist 3D pharmacophore from a set of antagonists. Comparing the two models, they surmised that an extra hydrogen bond feature in the agonist-derived 3D pharmacophore determines the activity of PTHR1 ligands as agonists or antagonists.…”

Mind the Gap – Deciphering GPCR Pharmacology Using 3D Pharmacophores and Artificial Intelligence

“…CPU03 showed much greater affinity to PTHR1 than CPU01, which was attributed to the fact that CPU03 fulfilled the agonist-based 3D pharmacophore model features to a greater extent that CPU01 was able to fulfill the antagonist-based model. Thus, these findings demonstrate the ability of 3D pharmacophore modeling to rationalize SARs by defining characteristics of PTHR1 agonists and antagonists [106].…”

“…Zhong and coworkers [106] generated a representative 3D pharmacophore agonist model from a set of parathyroid hormone-1 receptor (PTHR1) agonists, and a representative antagonist 3D pharmacophore from a set of antagonists. Comparing the two models, they surmised that an extra hydrogen bond feature in the agonist-derived 3D pharmacophore determines the activity of PTHR1 ligands as agonists or antagonists.…”

“…This method was recently employed to filter docking hypotheses of three serotonin receptor agonists at the 5-HT2BR in order to rationalize their differing degrees of biased agonism at the receptor [139]. Further examples of this use of 3D pharmacophores in the filtering of putative ligand binding conformations can be found in the studies detailed in section 2 [30,50,76,106].…”