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Journal of Computer-Aided Molecular Design

, Volume 32, Issue 2, pp 331–345 | Cite as

Validation of tautomeric and protomeric binding modes by free energy calculations. A case study for the structure based optimization of d-amino acid oxidase inhibitors

  • Zoltán Orgován
  • György G. Ferenczy
  • Thomas Steinbrecher
  • Bence Szilágyi
  • Dávid Bajusz
  • György M. Keserű
Article

Abstract

Optimization of fragment size d-amino acid oxidase (DAAO) inhibitors was investigated using a combination of computational and experimental methods. Retrospective free energy perturbation (FEP) calculations were performed for benzo[d]isoxazole derivatives, a series of known inhibitors with two potential binding modes derived from X-ray structures of other DAAO inhibitors. The good agreement between experimental and computed binding free energies in only one of the hypothesized binding modes strongly support this bioactive conformation. Then, a series of 1-H-indazol-3-ol derivatives formerly not described as DAAO inhibitors was investigated. Binding geometries could be reliably identified by structural similarity to benzo[d]isoxazole and other well characterized series and FEP calculations were performed for several tautomers of the deprotonated and protonated compounds since all these forms are potentially present owing to the experimental pKa values of representative compounds in the series. Deprotonated compounds are proposed to be the most important bound species owing to the significantly better agreement between their calculated and measured affinities compared to the protonated forms. FEP calculations were also used for the prediction of the affinities of compounds not previously tested as DAAO inhibitors and for a comparative structure–activity relationship study of the benzo[d]isoxazole and indazole series. Selected indazole derivatives were synthesized and their measured binding affinity towards DAAO was in good agreement with FEP predictions.

Graphical Abstract

Keywords

Free energy perturbation Tautomers Protomers Binding mode Optimization d-amino acid oxidase Inhibitor 

Notes

Acknowledgements

Financial support by the National Brain Research Program (project KTIA NAP_13) and by the Hungarian Science Foundation OTKA (project K111862) is gratefully acknowledged.

Supplementary material

10822_2018_97_MOESM1_ESM.docx (29 kb)
Supplementary material 1 (DOCX 28 KB)

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Medicinal Chemistry Research Group, Research Centre for Natural SciencesHungarian Academy of SciencesBudapestHungary
  2. 2.Schrödinger GmbHMannheimGermany

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