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Assessing protein–ligand binding modes with computational tools: the case of PDE4B

Abstract

In a first step in the discovery of novel potent inhibitor structures for the PDE4B family with limited side effects, we present a protocol to rank newly designed molecules through the estimation of their IC\(_{50}\) values. Our protocol is based on reproducing the linear relationship between the logarithm of experimental IC\(_{50}\) values [\(\log\)(IC\(_{50}\))] and their calculated binding free energies (\(\Delta G_\mathrm{binding}\)). From 13 known PDE4B inhibitors, we show here that (1) binding free energies obtained after a docking process by AutoDock are not accurate enough to reproduce this linear relationship; (2) MM-GB/SA post-processing of molecular dynamics (MD) trajectories of the top ranked AutoDock pose improves the linear relationship; (3) by taking into account all representative structures obtained by AutoDock and by averaging MM-GB/SA computations on a series of 40 independent MD trajectories, a linear relationship between \(\log\)(IC\(_{50}\)) and the lowest \(\Delta G_\mathrm{binding}\) is achieved with \(R^2=0.944\).

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Acknowledgements

G. Çifci, V. Aviyente received fundings from TUBITAK through Project 113Z001. G. Monard received fundings from CNRS through Project EDC25780. Computing resources used in this work were partially provided by the Centre de Calcul ROMEO of the Université de Reims Champagne-Ardenne, the State Planning Organization (DPT-2009K120520) and the Bogazici University Research Foundation (BAP-1856).

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Correspondence to Gerald Monard.

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Çifci, G., Aviyente, V., Akten, E.D. et al. Assessing protein–ligand binding modes with computational tools: the case of PDE4B. J Comput Aided Mol Des 31, 563–575 (2017). https://doi.org/10.1007/s10822-017-0024-7

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Keywords

  • PDE4B
  • IC50
  • Molecular docking
  • Molecular dynamics
  • MM-GB/SA