Rational Design of Drugs Targeting G-Protein-Coupled Receptors: Ligand Search and Screening.

G protein-coupled receptors (GPCRs) are transmembrane proteins that participate in many physiological processes and represent major pharmacological targets. Recent advances in structural biology of GPCRs have enabled the development of drugs based on the receptor structure (structure-based drug design, SBDD). SBDD utilizes information about the receptor-ligand complex to search for suitable compounds, thus expanding the chemical space of possible receptor ligands without the need for experimental screening. The review describes the use of structure-based virtual screening (SBVS) for GPCR ligands and approaches for the functional testing of potential drug compounds, as well as discusses recent advances and successful examples in the application of SBDD for the identification of GPCR ligands.

Rational Design of Drugs Targeting G-Protein-Coupled Receptors: A Structural Biology Perspective.

G protein-coupled receptors (GPCRs) play a key role in the transduction of extracellular signals to cells and regulation of many biological processes, which makes these membrane proteins one of the most important targets for pharmacological agents. A significant increase in the number of resolved atomic structures of GPCRs has opened the possibility of developing pharmaceuticals targeting these receptors via structure-based drug design (SBDD). SBDD employs information on the structure of receptor-ligand complexes to search for selective ligands without the need for an extensive high-throughput experimental ligand screening and can significantly expand the chemical space for ligand search. In this review, we describe the process of deciphering GPCR structures using X-ray diffraction analysis and cryoelectron microscopy as an important stage in the rational design of drugs targeting this receptor class. Our main goal was to present modern developments and key features of experimental methods used in SBDD of GPCR-targeting agents to a wide range of specialists.