Ligand Docking Methods to Recognize Allosteric Inhibitors for G-protein Coupled Receptors

Background: G-protein coupled receptors (GPCRs) are large protein families known to be important in many cellular processes. They are well known for their allosteric activation mechanisms. They are drug targets for several FDA-approved drugs. We have investigated the diversity of the ligand binding site for these class of proteins against their cognate ligands using computational docking, even if their structures are known in the ligand-complexed form. Results: The cognate ligand of some of these receptors dock at allosteric binding site, with better score than the binding at the conservative site. Further, ligands obtained from GLASS database, which consists of experimentally verified GPCR ligands, also show allosteric binding to GPCRs. The allosteric binders show strong affinity to the binding site, though the residues at the binding site are not conserved across GPCR subfamilies. Conclusions: Based on our computational approach it was found that the residues at the allosteric site are not as conserved as in the cognate binding site, which might explain the specificity of a particular GPCR. Further, for certain GPCRs, some of their known cognate ligands were predicted to have better binding preference towards the allosteric site than orthosteric site and therefore this computational approach can assist in the prediction of allosteric binders for GPCRs.