Discovery of P2Y 2 Receptor Antagonist Scaffolds through Virtual High-Throughput Screening.
Alexander NeumannIsaac AttahHaneen Al-HroubVigneshwaran NamasivayamChrista Elisabeth MüllerPublished in: Journal of chemical information and modeling (2022)
The human ATP- and UTP-activated P2Y 2 receptor (P2Y 2 R) is a G q protein-coupled receptor involved in several pathophysiological conditions including acute and chronic inflammation, cancer, and pain. Despite its potential as a novel drug target, only few P2Y 2 R antagonists have been developed so far, all of which suffer from severe drawbacks. These include (i) high polarity due to one or several negative charges resulting in low oral bioavailability, (ii) metabolic instability and generally poor pharmacokinetic properties, and/or (iii) lack of selectivity, which limits their utility for in vitro and in vivo studies aimed at target validation. In search of new druglike scaffolds for P2Y 2 R antagonists, we employed a structure-based virtual high-throughput screening approach utilizing the complex of a P2Y 2 R homology model with one of the most potent and selective orthosteric antagonists described so far, AR-C118925 ( 10 ). After virtual screening of 3.2 million molecules, 58 compounds were purchased and pharmacologically evaluated. Several novel antagonist scaffolds were discovered, and their binding modes at the human P2Y 2 R were analyzed by molecular docking studies. The investigated antagonists likely share a similar binding mode with 10 which includes accommodation of bulky, lipophilic groups in the putative orthosteric binding site of the P2Y 2 R. The discovered scaffolds and the elucidated structure-activity relationships provide a basis for the development of future drug candidates for the P2Y 2 R which have great potential as novel drugs.
Keyphrases
- molecular docking
- tissue engineering
- drug induced
- endothelial cells
- binding protein
- induced pluripotent stem cells
- chronic pain
- pluripotent stem cells
- molecular dynamics simulations
- small molecule
- papillary thyroid
- dna binding
- adverse drug
- intensive care unit
- case control
- squamous cell carcinoma
- current status
- protein protein
- squamous cell
- neuropathic pain
- anti inflammatory
- climate change
- electronic health record