Application of Multiscale Simulation Tools on GPCRs. An Example with Angiotensin II Type 1 Receptor

  • Ismail Erol
  • Busecan Aksoydan
  • Isik Kantarcioglu
  • Serdar DurdagiEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1824)


G protein-coupled receptors (GPCRs) represent the biggest class of membrane proteins included in signal transduction cascade across the biological lipid bilayers. They are essential target structures for cell signaling and are of great commercial interest to the pharmaceutical industry (~50% of marketed drugs and ~25% of top-selling drugs targeting this receptor family). Recent advances made in molecular biology and computational chemistry open new avenues for the design of new therapeutic compounds. Molecular biology has recently provided the crystal structures of a few ligand-bound GPCRs in active and inactive states, which can be used as accurate templates in modeling studies. Computational chemistry offers a range of simulation, multiscale modeling with ligand- and structure-based approaches, and virtual screening tools for definition and analysis of protein-ligand, protein-protein, and protein-DNA interactions. Development of new approaches and algorithms on statistical methods and free energy simulations help to predict novel optimal compounds. Integrated approach to drug discovery that combines quantum mechanics calculations, molecular docking, molecular dynamics (MD) simulations, quantitative structure-activity relationships (QSAR), and de novo design studies under a single umbrella can be used for decreasing the risk of false-positive results. Each method has its own pros and cons and, when used alone, is not likely to yield very useful results. However, when these methods are combined with positive feedback loops, they may enhance each other and successful drug leads may be obtained. Moreover, investigating the activation mechanisms and atomistic determinants of ligand binding to GPCR targets would allow greater safety in the human life.

Key words

GPCRs AT1 CCR5 CB1 Molecular modeling Docking Molecular dynamics (MD) simulations Homology modeling Protein engineering Ligand- and structure-based drug design 



This study is supported by The Scientific and Technological Research Council of Turkey (TÜBİTAK); Project No: 214Z122.


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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Ismail Erol
    • 1
  • Busecan Aksoydan
    • 1
  • Isik Kantarcioglu
    • 1
  • Serdar Durdagi
    • 1
    Email author
  1. 1.Department of Biophysics, Computational Biology and Molecular Simulations LaboratorySchool of Medicine, Bahcesehir UniversityIstanbulTurkey

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