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Theoretical Chemistry Accounts

, Volume 106, Issue 1–2, pp 2–9 | Cite as

How accurate can molecular dynamics/linear response and Poisson–Boltzmann/solvent accessible surface calculations be for predicting relative binding affinities? Acetylcholinesterase huprine inhibitors as a test case

  • X. Barril
  • J. L. Gelpí
  • J. M. López
  • M. Orozco
  • F. J. Luque
Regular article

Abstract.

This study examines the accuracy of molecular dynamics-linear response (MD/LR) and Poisson–Boltzmann/solvent accessible surface (PB/SAS) calculations to predict relative binding affinities. A series of acetylcholinesterase (AChE) huprine inhibitors has been chosen as a test system owing to the availability of free-energy (thermodynamic integration) calculations. The results obtained with the MD/LR approach point out a clear relationship between the experimental affinity and the electrostatic interaction energy alone for a subset of huprines, but the suitability of the MD/LR approach to predict the binding affinity of the whole series of compounds is limited. On the other hand, PB/SAS calculations show a marked dependence on both the computational protocol and the nature of the inhibitor–enzyme complex.

Key words: Free-energy calculations Linear response approximation Poisson Boltzmann/solvent accessible surface calculations Prediction of binding affinities Acetylcholinesterase inhibitors 

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Copyright information

© Springer-Verlag Berlin Heidelberg 2000

Authors and Affiliations

  • X. Barril
    • 1
  • J. L. Gelpí
    • 2
  • J. M. López
    • 1
  • M. Orozco
    • 2
  • F. J. Luque
    • 1
  1. 1. Departament de Físico-Química, Facultat de Farmàcia, Universitat de Barcelona, Av. Diagonal s/n, 08028 Barcelona, Spain e-mail: javier@far1.far.ub.esES
  2. 2. Departament de Bioquímica, Facultat de Química, Universitat de Barcelona, Av. Martí i Franqués 1, 08028 Barcelona, Spain e-mail: modesto@luz.bq.ub.esES

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