In Silico Pharmacology

, 5:16 | Cite as

Impact of protein–ligand solvation and desolvation on transition state thermodynamic properties of adenosine A2A ligand binding kinetics

  • Giuseppe Deganutti
  • Andrei Zhukov
  • Francesca DeflorianEmail author
  • Stephanie Federico
  • Giampiero Spalluto
  • Robert M. Cooke
  • Stefano Moro
  • Jonathan S. Mason
  • Andrea Bortolato
Original Research


Ligand–protein binding kinetic rates are growing in importance as parameters to consider in drug discovery and lead optimization. In this study we analysed using surface plasmon resonance (SPR) the transition state (TS) properties of a set of six adenosine A2A receptor inhibitors, belonging to both the xanthine and the triazolo-triazine scaffolds. SPR highlighted interesting differences among the ligands in the enthalpic and entropic components of the TS energy barriers for the binding and unbinding events. To better understand at a molecular level these differences, we developed suMetaD, a novel molecular dynamics (MD)—based approach combining supervised MD and metadynamics. This method allows simulation of the ligand unbinding and binding events. It also provides the system conformation corresponding to the highest energy barrier the ligand is required to overcome to reach the final state. For the six ligands evaluated in this study their TS thermodynamic properties were linked in particular to the role of water molecules in solvating/desolvating the pocket and the small molecules. suMetaD identified kinetic bottleneck conformations near the bound state position or in the vestibule area. In the first case the barrier is mainly enthalpic, requiring the breaking of strong interactions with the protein. In the vestibule TS location the kinetic bottleneck is instead mainly of entropic nature, linked to the solvent behaviour.


Metadynamics Supervised molecular dynamics Ligand binding kinetics SPR Biacore Molecular dynamics 

Supplementary material

40203_2017_37_MOESM1_ESM.docx (565 kb)
Supplementary material 1 (DOCX 565 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  • Giuseppe Deganutti
    • 1
  • Andrei Zhukov
    • 2
  • Francesca Deflorian
    • 2
    Email author
  • Stephanie Federico
    • 3
  • Giampiero Spalluto
    • 3
  • Robert M. Cooke
    • 2
  • Stefano Moro
    • 1
  • Jonathan S. Mason
    • 2
  • Andrea Bortolato
    • 2
  1. 1.Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological SciencesUniversity of PadovaPaduaItaly
  2. 2.Heptares Therapeutics Ltd.Welwyn Garden CityUK
  3. 3.Department of Chemical and Pharmaceutical SciencesUniversity of TriesteTriesteItaly

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