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Discovery of GPCR Ligands by Molecular Docking Screening: Novel Opportunities Provided by Crystal Structures
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). SeRC, Sweden.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). SeRC, Sweden.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). SeRC, Sweden.ORCID iD: 0000-0003-4623-2977
Number of Authors: 32015 (English)In: Current Topics in Medicinal Chemistry, ISSN 1568-0266, E-ISSN 1873-4294, Vol. 15, no 24, p. 2484-2503Article, review/survey (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2015. Vol. 15, no 24, p. 2484-2503
Keywords [en]
Agonist, Allosteric modulation, Drug discovery, Fragment-based lead discovery, G protein-coupled receptors, Library bias, Selectivity, Virtual screening
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:su:diva-160560DOI: 10.2174/1568026615666150701112853ISI: 000360375700003PubMedID: 26126906OAI: oai:DiVA.org:su-160560DiVA, id: diva2:1255454
Available from: 2018-10-12 Created: 2018-10-12 Last updated: 2018-10-12Bibliographically approved

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