Multiscale Molecular Modeling in G Protein-Coupled Receptor (GPCR)-Ligand Studies

G protein-coupled receptors (GPCRs) are major drug targets due to their ability to facilitate signal transduction across cell membranes, a process that is vital for many physiological functions to occur. The development of computational technology provides modern tools that permit accurate studies of the structures and properties of large chemical systems, such as enzymes and GPCRs, at the molecular level. The advent of multiscale molecular modeling permits the implementation of multiple levels of theories on a system of interest, for instance, assigning chemically relevant regions to high quantum mechanics (QM) level of theory while treating the rest of the system using classical force field (molecular mechanics (MM) potential). Multiscale QM/MM molecular modeling have far-reaching applications in the rational design of GPCR drugs/ligands by affording precise ligand binding configurations through the consideration of conformational plasticity. This enables the identification of key binding site residues that could be targeted to manipulate GPCR function. This review will focus on recent applications of multiscale QM/MM molecular simulations in GPCR studies that could boost the efficiency of future structure-based drug design (SBDD) strategies.