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Challenges and Opportunities in Drug Discovery of Biased Ligands

  • Ismael Rodríguez-Espigares
  • Agnieszka A. Kaczor
  • Tomasz Maciej Stepniewski
  • Jana SelentEmail author
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1705)

Abstract

The observation of biased agonism in G protein-coupled receptors (GPCRs) has provided new approaches for the development of more efficacious and safer drugs. However, in order to rationally design biased drugs, one must understand the molecular basis of this phenomenon. Computational approaches can help in exploring the conformational universe of GPCRs and detecting conformational states with relevance for distinct functional outcomes. This information is extremely valuable for the development of new therapeutic agents that promote desired conformational receptor states and responses while avoiding the ones leading to undesired side-effects.

This book chapter intends to introduce the reader to powerful computational approaches for sampling the conformational space of these receptors, focusing first on molecular dynamics and the analysis of the produced data through methods such as dimensionality reduction, Markov State Models and adaptive sampling. Then, we show how to seek for compounds that target distinct conformational states via docking and virtual screening. In addition, we describe how to detect receptor-ligand interactions that drive signaling bias and comment current challenges and opportunities of presented methods.

Key words

G protein-coupled receptor Receptor plasticity Conformational space Signaling bias Drug discovery 

Notes

Acknowledgments

I.R.-E. acknowledges financial support from Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya (2015 FI_B00145). The paper was developed using the equipment purchased within the project “The equipment of innovative laboratories doing research on new medicines used in the therapy of civilization and neoplastic diseases” within the Operational Program Development of Eastern Poland 2007-2013, Priority Axis I Modern Economy, operations I.3 Innovation promotion.

T.M.S. acknowledges financial support from Hospital del Mar Medical Research Institute.

Finally, J.S. acknowledges financial support from Instituto de Salud Carlos III FEDER (PI15/00460).

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Copyright information

© Springer Science+Business Media LLC 2018

Authors and Affiliations

  • Ismael Rodríguez-Espigares
    • 1
  • Agnieszka A. Kaczor
    • 2
    • 3
  • Tomasz Maciej Stepniewski
    • 1
  • Jana Selent
    • 1
    Email author
  1. 1.Department of Experimental and Health Sciences, Research Programme on Biomedical Informatics (GRIB)Hospital del Mar Medical Research Institute (IMIM), Pompeu Fabra University (UPF)BarcelonaSpain
  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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