The GPCR relaxin family peptide receptor 1 (RXFP1) mediates the action of relaxin peptide hormone such as its tissue remodeling and antifibrotic effectsin various organs.  Small molecule agonist of RXFP1 as alternative to relaxin hormone  may have important pharmocological applications for several diseases such as heart failure and fibrosis. The first small molecule agonists of RXFP1 were recently identified from a high throughtput screen using a homogenous cell-based cAMP assay (Chen et al, 2012). Optimization of the hit compounds resulted in a series of highly potent and RXFP1 selective agonists with low cytotoxicity, excellent in vitro ADME, and pharmacokinetic properties (Xiao et al). To better understand the molecular basis of their action, we developed a structural model of the small molecules binding to RXFP1. The binding model of the agonist to RXFP1 was built using a protocol combining homology modeling, docking, and MD simulations. Analysis showed that the molecule binds to RXFP1 in a manner similar to the agonist binding complex of �2AR. Unique to RXFP1, however, is the involvement of extracellular loop 3 (ECL3) of 7TM domain whose extensive H-bonding is crucial to the observed selectivity of the compounds for RXFP1 over other related receptors. Comparison of the active conformation of RXFP1 to the inactive binding mode indicated that ECL3 undergoes a significant conformational change upon agonist binding. In addition, structural models of the LRR domain of RXFP1 were also investigated to gain insight into their potential binding interactions with relaxin. Taken together, these results revealed a valuable information on the structural basis and molecular mechanism of activation and selectivity of the small molecule agonists for RXFP1, thus providing a useful tool for future optimization of the lead series.

Structural modeling of the relaxin peptide receptor and its small molecule agonists

245th National Meeting (2013)

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