Computational approaches for ligand discovery and design in class-A G protein- coupled receptors

Curr Pharm Des. 2013;19(12):2216-36. doi: 10.2174/1381612811319120009.


Our structural understanding of the superfamily of G-protein coupled receptors, a group of targets of utmost pharmacological importance, has improved dramatically in the last few years. This was directly translated in an increase of both the number and the relevance of computer-assisted drug design efforts devoted to these receptors. The field, which had been greatly influenced by ligand-based methods, has experienced a radical transformation with a number of successful structure-based ligand design and ligand discovery studies. This revolution has been accompanied by the exponential increase of computational resources, and as a result the scenario in GPCR structural and chemical studies is now more complex and richer than ever. Virtual screens, both structure- and ligand-based, co-exist with accurate computational characterizations of the receptor conformational dynamics and of the energy landscapes of receptor-ligand interactions. We here provide an integrated and updated view of the different computational techniques applied to the ligand design of GPCRs. Particular emphasis is put on the studies that take into account the novel structural information of GPCRs, together with those that consider the enormous amount of chemical information accumulated on these receptors in the last decades. Indeed, we propose that proper combinations of the different computational techniques: ligand-based, structure-based and molecular dynamics studies, should be performed to better integrate all available information whenever possible. With this in mind, a major impact of computational technologies in the ligand design on GPCRs is expected in the forthcoming years.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Computational Biology* / trends
  • Drug Design*
  • Drug Discovery* / trends
  • Drug Evaluation, Preclinical
  • Humans
  • Ligands
  • Molecular Conformation
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Pharmaceutical Preparations / chemistry*
  • Pharmaceutical Preparations / metabolism
  • Pharmacology / methods*
  • Pharmacology / trends
  • Protein Stability / drug effects
  • Quantitative Structure-Activity Relationship
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, G-Protein-Coupled / chemistry*
  • Receptors, G-Protein-Coupled / metabolism


  • Ligands
  • Pharmaceutical Preparations
  • Receptors, G-Protein-Coupled