Journal of Computer-Aided Molecular Design

, Volume 29, Issue 12, pp 1109–1122 | Cite as

Predicting the relative binding affinity of mineralocorticoid receptor antagonists by density functional methods

  • Katarina RoosEmail author
  • Anders Hogner
  • Derek Ogg
  • Martin J. Packer
  • Eva Hansson
  • Kenneth L. Granberg
  • Emma Evertsson
  • Anneli NordqvistEmail author


In drug discovery, prediction of binding affinity ahead of synthesis to aid compound prioritization is still hampered by the low throughput of the more accurate methods and the lack of general pertinence of one method that fits all systems. Here we show the applicability of a method based on density functional theory using core fragments and a protein model with only the first shell residues surrounding the core, to predict relative binding affinity of a matched series of mineralocorticoid receptor (MR) antagonists. Antagonists of MR are used for treatment of chronic heart failure and hypertension. Marketed MR antagonists, spironolactone and eplerenone, are also believed to be highly efficacious in treatment of chronic kidney disease in diabetes patients, but is contra-indicated due to the increased risk for hyperkalemia. These findings and a significant unmet medical need among patients with chronic kidney disease continues to stimulate efforts in the discovery of new MR antagonist with maintained efficacy but low or no risk for hyperkalemia. Applied on a matched series of MR antagonists the quantum mechanical based method gave an R2 = 0.76 for the experimental lipophilic ligand efficiency versus relative predicted binding affinity calculated with the M06-2X functional in gas phase and an R2 = 0.64 for experimental binding affinity versus relative predicted binding affinity calculated with the M06-2X functional including an implicit solvation model. The quantum mechanical approach using core fragments was compared to free energy perturbation calculations using the full sized compound structures.

Graphical Abstract


Nuclear hormone receptor QM FEP DFT 



β-Site APP cleaving enzyme


Density functional theory


Free energy perturbation


Ligand binding domain


Ligand binding pocket


Lipophilic ligand efficiency


Logarithm of the distribution coefficient in octanol/water at pH 7.4


Minimum discriminatory ratio


Mineralocorticoid receptor


Quantum mechanical


Replica exchange with solute tempering


Scintillation proximity assay



The authors thank DMPK for logD7.4 profiling of the compounds, Marianne Wedin and Ulla Karlsson for performing MR binding assay experiments. We also thank Mats Svensson for valuable discussions and scientific input.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10822_2015_9880_MOESM1_ESM.doc (1.1 mb)
Supplementary material 1 (DOC 1147 kb)
10822_2015_9880_MOESM2_ESM.pdf (74 kb)
Supplementary material 2 (PDF 73 kb)
10822_2015_9880_MOESM3_ESM.pdf (17 kb)
Supplementary material 3 (PDF 17 kb)


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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Katarina Roos
    • 1
    Email author
  • Anders Hogner
    • 2
  • Derek Ogg
    • 3
  • Martin J. Packer
    • 4
  • Eva Hansson
    • 5
  • Kenneth L. Granberg
    • 2
  • Emma Evertsson
    • 1
  • Anneli Nordqvist
    • 2
    Email author
  1. 1.RIA Medicinal ChemistryAstraZenecaMölndalSweden
  2. 2.CVMD Medicinal ChemistryAstraZenecaMölndalSweden
  3. 3.Discovery SciencesAstraZenecaMacclesfieldUK
  4. 4.Oncology Medicinal ChemistryAstraZenecaMacclesfieldUK
  5. 5.Discovery SciencesAstraZenecaMölndalSweden

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