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Discovery of GPCR Ligands by Molecular Docking Screening: Novel Opportunities Provided by Crystal Structures

[ Vol. 15 , Issue. 24 ]

Author(s):

David Rodríguez, Anirudh Ranganathan and Jens Carlsson   Pages 2484 - 2503 ( 20 )

Abstract:


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.

Affiliation:

Science for Life Laboratory, Box 1031. 17121 Solna, Sweden.

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