A Fragment-Based Computational Method for Designing GPCR Ligands

G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and the most important drug targets. With the technology breakthroughs in the structural determination of GPCRs by X-ray crystallography and cryo-electron microscopy (cryo-EM), more than 300 GPCR-ligand complex structures have been reported since 2007, covering around 60 unique GPCRs. Such abundant structural information provides a good opportunity for structure-based design of ligands targeting GPCRs. In this study, we have developed a fragment-based computational method for GPCR ligand design. We first extracted the characteristic interaction patterns (CIPs) on the binding interfaces between GPCRs and their ligands. The CIPs were used as queries to search ligand derived fragments, which could form similar interaction patterns with GPCRs. Then, the hit fragments were assembled into whole molecules by using the AutoT&T2 software. At the end, we chose β-adrenergic receptor (β-AR) and muscarinic acetylcholine receptor (mACh...