The relaxin family peptide receptor 1 (RXFP1) is a member of class A relaxin/insulin-like family of GPCR receptors, which mediates the action of relaxin including its tissue remodeling and antifibrotic effects. The wide range of effects and applications of relaxin peptide underscores the importance of this hormone in human physiology and disease. Small-molecule agonists of RXFPs have attracted great interest as valuable tools in understanding of relaxin biology and providing useful therapeutic approaches for chronic diseases such as heart failure and fibrosis. The first small molecule agonists of RXFP1 have been recently identified from a high throughput screen using a homogenous cell-based cAMP assay. Optimization of the hit compounds resulted in a series of highly potent and RXFP1 selective agonists with low cytotoxicity, and excellent <i>in vitro</i> ADME and pharmacokinetic properties. Further site-directed mutagenesis studies in combination with computational modeling, docking, and molecular dynamic simulations revealed structural basis of the small molecule binding to RXFP1, providing insights into the mechanism of receptor activation and species specificity among different RXFPs. To identify novel agonist of RXFP1, large scale database in silico screening was performed using both ligand and structure-based virtual screening protocols. The results of identified compounds from VS in comparison with high throughput screening (HTS) are discussed.

Structural modeling and identification of small molecule agonists of human relaxin family peptide receptor 1

253rd National Meeting (2017)

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