Structure-Based Virtual Screening for Ligands of G Protein-Coupled Receptors: What Can Molecular Docking Do for You?

Research output: Contribution to journalReviewpeer-review

Documents

  • Fulltext

    Final published version, 3.67 MB, PDF document

G protein-coupled receptors (GPCRs) constitute the largest family of membrane proteins in the human genome and are important therapeutic targets. During the last decade, the number of atomic -resolution structures of GPCRs has increased rapidly, providing insights into drug binding at the molecular level. These breakthroughs have created excitement regarding the potential of using structural information in ligand design and initiated a new era of rational drug discovery for GPCRs. The molecular docking method is now widely applied to model the threedimensional structures of GPCR-ligand complexes and screen for chemical probes in large compound libraries. In this review article, we first summarize the current structural coverage of the GPCR superfamily and the understanding of receptor-ligand interactions at atomic resolution. We then present the general workflow of structure-based virtual screening and strategies to discover GPCR ligands in chemical libraries. We assess the state of the art of this research field by summarizing prospective applications of virtual screening based on experimental structures. Strategies to identify compounds with specific efficacy and selectivity profiles are discussed, illustrating the opportunities and limitations of the molecular docking method. Our overview shows that structure-based virtual screening can discover novel leads and will be essential in pursuing the next generation of GPCR drugs. Significance Statement--Extraordinary advances in the structural biology of G protein-coupled receptors have revealed the molecular details of ligand recognition by this large family of therapeutic targets, providing novel avenues for rational drug design. Structure-based docking is an efficient computational approach to identify novel chemical probes from large compound libraries, which has the potential to accelerate the development of drug candidates.

Original languageEnglish
JournalPharmacological Reviews
Volume73
Issue number4
Pages (from-to)527-565
ISSN0031-6997
DOIs
Publication statusPublished - 2021

    Research areas

  • STRUCTURE-BASED DISCOVERY, ADENOSINE A(2A) RECEPTOR, STRUCTURE-BASED PREDICTION, KAPPA-OPIOID RECEPTOR, FRAGMENT-LIKE LIGANDS, CRYSTAL-STRUCTURE, DRUG DISCOVERY, BETA(2)-ADRENERGIC RECEPTOR, ALLOSTERIC MODULATORS, INTERNATIONAL UNION

Number of downloads are based on statistics from Google Scholar and www.ku.dk


No data available

ID: 291671652