Molecular-Docking-Based Drug Design and Discovery

Abstract

Currently 30-50% of drug targets are G Protein-Coupled Receptors (GPCRs). However, the clinical useful drugs for targeting GPCR have been limited by the lack of subtype selectivity or efficacy, leading to undesirable side effects. To develop subtype-selective GPCR ligands with desired molecular properties, better understanding is needed of the pharmacophore elements and of the binding mechanism required for subtype selectivity. To illustrate these issues, we describe here three successful applications to understand the binding mechanism associated with subtype selectivity: 5-HT2B (5-Hydroxytryptamine, 5-HT) serotonin receptor (HT2BR), H3 histamine receptor (H3HR) and A3 adenosine receptor (A3AR). The understanding of structure-function relationships among individual types and subtypes of GPCRs gained from such computational predictions combined with experimental validation and testing is expected the development of new highly selective and effective ligands to address such diseases while minimizing side-effects.