Structure-Based Prediction of G-Protein-Coupled Receptor Ligand Function: A beta-Adrenoceptor Case Study

摘要

The spectacular advances in G-protein-coupled receptor (GPCR) structure determination have opened up new possibilities for structure-based GPCR ligand discovery. The structure-based prediction of whether a ligand stimulates (full/partial agonist), blocks (antagonist), or reduces (inverse agonist) GPCR signaling activity is, however, still challenging. A total of 31 beta(1) (beta R-1) and beta(2) (beta R-2) adrenoceptor crystal structures, including antagonist, inverse agonist, and partial/full agonist-bound structures, allowed us to explore the possibilities and limitations of structure-based prediction of GPCR ligand function. We used all unique protein ligand interaction fingerprints (IFPs) derived from all ligand-bound beta-adrenergic crystal structure monomers to post-process the docking poses of known beta R-1/beta R-2 partial/full agonists, antagonists/inverse agonists, and physicochemically similar decoys in each of the beta R-1/beta R-2 structures. The systematic analysis of these 1920 unique IFP structure combinations offered new insights into the relative impact of protein conformation and IFP scoring on selective virtual screening (VS) for ligands with a specific functional effect. Our studies show that ligands with the same function can be efficiently classified on the basis of their protein ligand interaction profile. Small differences between the receptor conformation (used for docking) and reference IFP (used for scoring of the docking poses) determine, however, the enrichment of specific ligand types in VS hit lists. Interestingly, the selective enrichment of partial/full agonists can be achieved by using agonist IFPs to post-process docking poses in agonist-bound as well as antagonist-bound structures. We have identified optimal structure IFP combinations for the identification and discrimination of antagonists/inverse agonist and partial/full agonists, and defined a predicted IFP for the small full agonist norepinephrine that gave the highest retrieval rate of agonists over antagonists for all structures (with an enrichment factor of 46 for agonists and 8 for antagonists on average at a 1% false-positive rate). This beta-adrenoceptor case study provides new insights into the opportunities for selective structure-based discovery of GPCR ligands with a desired function and emphasizes the importance of IFPs in scoring docking poses.