Matching Cavities in G Protein-Coupled Receptors to Infer Ligand-Binding Sites

To understand the activity and cross reactivity of ligands and
G protein-coupled receptors, we take stock of relevant existing receptor
mutation, sequence, and structural data to develop a statistically
robust and transparent scoring system. Our method evaluates the viability
of binding of any ligand for any GPCR sequence of amino acids. This enabled us to explore the binding
repertoire of both receptors and ligands, relying solely on correlations
between carefully identified receptor features and without requiring
any chemical information about ligands. This study suggests that sequence
similarity at specific binding pockets can predict relative affinity
of ligands; enabling recovery of over 80% of known ligands for a withheld
receptor and almost 80% of known receptors for a ligand. The method
enables qualitative prediction of ligand binding for all nonredundant
human G protein-coupled receptors.