Understanding allosteric and biased GPCR computer simulations and mutagenesis

Strongly biased allosteric ligands that modify the response pattern of the receptor can yield therapeutics with hiter efficacy or fewer side effects.

Structure-based virtual screening methods scan molecular databases against a cavity of the receptor to select its like y ligands. For allosteric GPCR ligands, such design is limited by the ability to find drug-compatible pockets outside the main receptor cavity, by the ability to screen molecules based on receptor interactions, especially within membrane, and by the level of understanding of allosteric and (or) biased ligand mechanism of action.<br><br>To help identify allosteric sites, we combine and compare in silico approaches to detect allosteric pockets for a promising GPCR and then evaluate their functional relevance by in vitro mutagenesis studies and combine experimental data with computer simulations to gain insights for possible ligand design.