Binding site identification of G protein-coupled receptors through a 3D Zernike polynomials-based method: application to C. elegans olfactory receptors

Studying the binding processes of G protein-coupled receptors (GPCRs) proteins is of particular interest both to better understand the molecular mechanisms that regulate the signaling between the extracellular and intracellular environment and for drug design purposes. In this study, we propose a new computational approach for the identification of the binding site for a specific ligand on a GPCR. The method is based on the Zernike polynomials and performs the ligand-GPCR association through a shape complementarity analysis of the local molecular surfaces. The method is parameter-free and it can distinguish, working on hundreds of experimentally GPCR-ligand complexes, binding pockets from randomly sampled regions on the receptor surface, obtaining an Area Under ROC curve of 0.77. Given its importance both as a model organism and in terms of applications, we thus investigated the olfactory receptors of the C. elegans, building a list of associations between 21 GPCRs belonging to its olfactory neurons and a set of possible ligands. Thus, we can not only carry out rapid and efficient screenings of drugs proposed for GPCRs, key targets in many pathologies, but also we laid the groundwork for computational mutagenesis processes, aimed at increasing or decreasing the binding affinity between ligands and receptors.