Journal of Computer-Aided Molecular Design

, Volume 31, Issue 6, pp 563–575

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

  • Gülşah Çifci
  • Viktorya Aviyente
  • E. Demet Akten
  • Gerald Monard
Article
  • 180 Downloads

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 \(R^2=0.944\).

Keywords

PDE4B IC50 Molecular docking Molecular dynamics MM-GB/SA 

Supplementary material

10822_2017_24_MOESM1_ESM.pdf (268 kb)
Supplementary material 1 (pdf 269 KB)

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Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  1. 1.Department of ChemistryBoğaziçi UniversityBebekTurkey
  2. 2.Bioinformatics and GeneticKadir Has UniversityCibaliTurkey
  3. 3.Université de Lorraine, UMR 7565 SRSMCVandoeuvre-les-NancyFrance
  4. 4.CNRS, UMR 7565 SRSMCVandoeuvre-les-NancyFrance

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