G protein-coupled receptors (GPCRs) constitute the largest group of human membrane proteins
and have received significant attention in drug discovery for their important roles in physiological
processes. Drug development for GPCRs has been remarkably successful and several of the most
profitable pharmaceuticals on the market target members of this superfamily. Breakthroughs in structural
biology for GPCRs have revealed how their binding sites recognize extracellular molecules at the
atomic level. High-resolution crystal structures of GPCR-drug complexes capturing different receptor
conformations are now available, which have provided insights into how ligands stabilize different functional states. Recently,
the basis for subtype selectivity and novel allosteric binding sites has also been revealed by crystal structures.
These accomplishments provide exciting opportunities to identify novel GPCR ligands using in silico structure-based
methods such as molecular docking. Increased computational power now enables docking screens of large chemical libraries
to identify molecules that complement GPCR binding sites, which may provide possibilities to identify ligands
with tailored pharmacological properties. This review focuses on prospective docking screens against GPCRs and how
this technique can be used to identify lead candidates with specific signaling or selectivity profiles. The current state of
this field suggests that molecular docking, in combination with further understanding of GPCR signaling, will play an important
role in future drug discovery.
Keywords: Agonist, Allosteric modulation, Drug discovery, Fragment-based lead discovery, G protein-coupled receptors,
Library bias, Selectivity, Virtual screening.
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