Opportunities and Challenges in the Discovery of Allosteric Modulators of GPCRs

  • Damian Bartuzi
  • Agnieszka A. Kaczor
  • Dariusz Matosiuk
Part of the Methods in Molecular Biology book series (MIMB, volume 1705)


From the pharmacological point of view, allosteric modulators may present numerous advantages over orthosteric ligands. Growing availability of novel tools and experimental data provides a tempting opportunity to apply computational methods to improve known modulators and design novel ones. However, recent progress in understanding of complexity of allostery increases awareness of problems involved in design of modulators with desired properties. Deeper insight into phenomena such as probe dependence, altering signaling bias with minor changes in ligand structure, as well as influence of subtle endogenous allosteric factors turns out to be fundamental. These effects make the design of a modulator with precise pharmacological outcome a very challenging task, and need to be taken into consideration throughout the design process. In this chapter, we focus on nuances of targeting GPCR allosteric sites in computational drug design efforts, in particular with application of docking, virtual screening, and molecular dynamics.

Key words

Allostery Allosteric modulation GPCR Molecular dynamics Molecular docking Virtual screening Probe dependence Signal transduction Structure-based drug design Protein dynamics 


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Copyright information

© Springer Science+Business Media LLC 2018

Authors and Affiliations

  • Damian Bartuzi
    • 1
  • Agnieszka A. Kaczor
    • 2
    • 3
  • Dariusz Matosiuk
    • 1
  1. 1.Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modelling LabMedical University of LublinLublinPoland
  2. 2.Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modelling Lab, Faculty of Pharmacy with Division of Medical AnalyticsMedical University of LublinLublinPoland
  3. 3.Department of Pharmaceutical Chemistry, School of PharmacyUniversity of Eastern FinlandKuopioFinland

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