Journal of Computer-Aided Molecular Design

, Volume 29, Issue 12, pp 1137–1149 | Cite as

Dynamics and structural determinants of ligand recognition of the 5-HT6 receptor

  • Márton Vass
  • Balázs Jójárt
  • Ferenc Bogár
  • Gábor Paragi
  • György M. Keserű
  • Ákos Tarcsay


In order to identify molecular models of the human 5-HT6 receptor suitable for virtual screening, homology modeling and membrane-embedded molecular dynamics simulations were performed. Structural requirements for robust enrichment were assessed by an unbiased chemometric analysis of enrichments from retrospective virtual screening studies. The two main structural features affecting enrichment are the outward movement of the second extracellular loop and the formation of a hydrophobic cavity deep in the binding site. These features appear transiently in the trajectories and furthermore the stretches of uniformly high enrichment may only last 4–10 ps. The formation of the inner hydrophobic cavity was also linked to the active-like to inactive-like transition of the receptor, especially the so-called connector region. The best structural models provided significant and robust enrichment over three independent ligand sets.


5-HT6 receptor Molecular dynamics Docking Enrichment Virtual screening 





Alzheimer’s disease


Boltzmann-Enhanced Discrimination Receiver Operator Characteristic area under the curve


Extracellular loop


GPCR Decoy Database


G protein-coupled receptor


Intracellular loop


Induced fit docking




Root mean square deviation (of atomic positions)



This work was supported by the National Brain Research Program KTIA-NAP-13-1-2013-0001. V.M., Gy.M.K. and Á.T. participate in the European Cooperation in Science and Technology (COST) Action CM1207: GPCR-Ligand Interactions, Structures, and Transmembrane Signalling: a European Research Network (GLISTEN). G.P. would like to thank for the financial support of the Marie Curie Intra European Fellowship within the 7th European Community Framework Programme.

Supplementary material

10822_2015_9883_MOESM1_ESM.pdf (2.5 mb)
Supplementary material 1 (PDF 2517 kb)


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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Márton Vass
    • 1
    • 6
  • Balázs Jójárt
    • 2
  • Ferenc Bogár
    • 3
  • Gábor Paragi
    • 3
    • 4
  • György M. Keserű
    • 5
  • Ákos Tarcsay
    • 1
    • 7
  1. 1.Discovery ChemistryGedeon Richter Plc.BudapestHungary
  2. 2.Department of Chemical Informatics, Faculty of EducationUniversity of SzegedSzegedHungary
  3. 3.MTA SZTE Supramolecular and Nanostructured Materials Research Group, Hungarian Academy of SciencesUniversity of SzegedSzegedHungary
  4. 4.Department of Theoretical ChemistryVU University AmsterdamAmsterdamThe Netherlands
  5. 5.Research Centre for Natural SciencesHungarian Academy of SciencesBudapestHungary
  6. 6.Division of Medicinal Chemistry, Faculty of Science, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS)VU University AmsterdamAmsterdamThe Netherlands
  7. 7.ChemAxon Ltd.BudapestHungary

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