Importance of Structure and Dynamics in the Rational Drug Design of G Protein-Coupled Receptor (GPCR) Modulators

G protein-coupled receptors (GPCRs) are one of the largest classes of human membrane proteins. The aptitude of GPCRs to assume multiple conformational states enables them to modulate numerous signaling pathways, hence making GPCRs viable drug targets for multiple diseases such as cancer, cardiac diseases, and metabolic disorders. Recent GPCR studies, both experimental and computational, have highlighted the structural significance of GPCRs and have prioritized exploration of their dynamics to gain insights into their physiological role. The modernization of computational methods, such as homology modeling, virtual screening, and molecular docking, to include GPCR dynamics via computer simulation and enhanced sampling methods, has resulted in promising improvements in the reliability of structure-based drug discovery. In this chapter, we will highlight advances in computational strategies used to examine GPCRs, illustrating the importance of receptor dynamics, water dynamics, and exploration of diverse binding sites in the rational design of GPCR ligands.