Journal of Molecular Modeling

, 21:284 | Cite as

Towards predictive docking at aminergic G-protein coupled receptors

  • Jan JakubíkEmail author
  • Esam E. El-Fakahany
  • Vladimír Doležal
Original Paper


G protein-coupled receptors (GPCRs) are hard to crystallize. However, attempts to predict their structure have boomed as a result of advancements in crystallographic techniques. This trend has allowed computer-aided molecular modeling of GPCRs. We analyzed the performance of four molecular modeling programs in pose evaluation of re-docked antagonists / inverse agonists to 11 original crystal structures of aminergic GPCRs using an induced fit-docking procedure. AutoDock and Glide were used for docking. AutoDock binding energy function, GlideXP, Prime MM-GB/SA, and YASARA binding function were used for pose scoring. Root mean square deviation (RMSD) of the best pose ranged from 0.09 to 1.58 Å, and median RMSD of the top 60 poses ranged from 1.47 to 3.83 Å. However, RMSD of the top pose ranged from 0.13 to 7.33 Å and ranking of the best pose ranged from the 1st to 60th out of 60 poses. Moreover, analysis of ligand–receptor interactions of top poses revealed substantial differences from interactions found in crystallographic structures. Bad ranking of top poses and discrepancies between top docked poses and crystal structures render current simple docking methods unsuitable for predictive modeling of receptor–ligand interactions. Prime MM-GB/SA optimized for 3NY9 by multiple linear regression did not work well at 3NY8 and 3NYA, structures of the same receptor with different ligands. However, 9 of 11 trajectories of molecular dynamics simulations by Desmond of top poses converged with trajectories of crystal structures. Key interactions were properly detected for all structures. This procedure also worked well for cross-docking of tested β2-adrenergic antagonists. Thus, this procedure represents a possible way to predict interactions of antagonists with aminergic GPCRs.


Induced-fit docking Pose scoring Molecular dynamics Ligand-receptor interaction 



This work was supported by the Academy of Sciences of the Czech Republic project [AV0Z 50110509] and support [RVO:67985823], the Czech Science Foundation grants [305/09/0681], [P304/12/G069] and [14-05696S]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Supplementary material

894_2015_2824_MOESM1_ESM.pdf (6.9 mb)
Text S1 Ligand interaction diagrams of target, top, and best pose as well as histograms of ligand–receptor interactions over the trajectory of MD simulation of crystal structure and top pose structure of all 11 receptors tested are available in Supporting Information Text File S1. (PDF 7036 kb) (3 mb)
Data S2 The top and the best poses of all tested ligand-receptor complexes in pdb format are available in Supporting Information Data File S2. (ZIP 3047 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Jan Jakubík
    • 1
    Email author
  • Esam E. El-Fakahany
    • 2
  • Vladimír Doležal
    • 1
  1. 1.Institute of PhysiologyAcademy of Sciences of the Czech RepublicPragueCzech Republic
  2. 2.Department of Experimental and Clinical PharmacologyUniversity of Minnesota College of PharmacyMinneapolisUSA

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