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Binding affinities of the farnesoid X receptor in the D3R Grand Challenge 2 estimated by free-energy perturbation and docking

Olsson, Martin A. LU ; García-Sosa, Alfonso T. and Ryde, Ulf LU (2018) In Journal of Computer-Aided Molecular Design 32(1). p.211-224
Abstract

We have studied the binding of 102 ligands to the farnesoid X receptor within the D3R Grand Challenge 2016 blind-prediction competition. First, we employed docking with five different docking software and scoring functions. The selected docked poses gave an average root-mean-squared deviation of 4.2 Å. Consensus scoring gave decent results with a Kendall’s τ of 0.26 ± 0.06 and a Spearman’s ρ of 0.41 ± 0.08. For a subset of 33 ligands, we calculated relative binding free energies with free-energy perturbation. Five transformations between the ligands involved a change of the net charge and we implemented and benchmarked a semi-analytic correction (Rocklin et al., J Chem Phys 139:184103, 2013) for artifacts caused by the periodic boundary... (More)

We have studied the binding of 102 ligands to the farnesoid X receptor within the D3R Grand Challenge 2016 blind-prediction competition. First, we employed docking with five different docking software and scoring functions. The selected docked poses gave an average root-mean-squared deviation of 4.2 Å. Consensus scoring gave decent results with a Kendall’s τ of 0.26 ± 0.06 and a Spearman’s ρ of 0.41 ± 0.08. For a subset of 33 ligands, we calculated relative binding free energies with free-energy perturbation. Five transformations between the ligands involved a change of the net charge and we implemented and benchmarked a semi-analytic correction (Rocklin et al., J Chem Phys 139:184103, 2013) for artifacts caused by the periodic boundary conditions and Ewald summation. The results gave a mean absolute deviation of 7.5 kJ/mol compared to the experimental estimates and a correlation coefficient of R2 = 0.1. These results were among the four best in this competition out of 22 submissions. The charge corrections were significant (7–8 kJ/mol) and always improved the results. By employing 23 intermediate states in the free-energy perturbation, there was a proper overlap between all states and the precision was 0.1–0.7 kJ/mol. However, thermodynamic cycles indicate that the sampling was insufficient in some of the perturbations.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Bennett acceptance ratio, Charge transformations, D3R Grand Challenge 2016, Docking, Drug design data resource, Free-energy perturbation, Ligand binding, Periodic boundary conditions, Quantum-polarised ligand docking
in
Journal of Computer-Aided Molecular Design
volume
32
issue
1
pages
211 - 224
publisher
Kluwer
external identifiers
  • scopus:85028805060
ISSN
0920-654X
DOI
10.1007/s10822-017-0056-z
language
English
LU publication?
yes
id
a0337515-8da8-4dfc-a5f0-250c751c24f0
date added to LUP
2017-09-26 10:06:44
date last changed
2018-03-28 03:00:13
@article{a0337515-8da8-4dfc-a5f0-250c751c24f0,
  abstract     = {<p>We have studied the binding of 102 ligands to the farnesoid X receptor within the D3R Grand Challenge 2016 blind-prediction competition. First, we employed docking with five different docking software and scoring functions. The selected docked poses gave an average root-mean-squared deviation of 4.2 Å. Consensus scoring gave decent results with a Kendall’s τ of 0.26 ± 0.06 and a Spearman’s ρ of 0.41 ± 0.08. For a subset of 33 ligands, we calculated relative binding free energies with free-energy perturbation. Five transformations between the ligands involved a change of the net charge and we implemented and benchmarked a semi-analytic correction (Rocklin et al., J Chem Phys 139:184103, 2013) for artifacts caused by the periodic boundary conditions and Ewald summation. The results gave a mean absolute deviation of 7.5 kJ/mol compared to the experimental estimates and a correlation coefficient of R<sup>2</sup> = 0.1. These results were among the four best in this competition out of 22 submissions. The charge corrections were significant (7–8 kJ/mol) and always improved the results. By employing 23 intermediate states in the free-energy perturbation, there was a proper overlap between all states and the precision was 0.1–0.7 kJ/mol. However, thermodynamic cycles indicate that the sampling was insufficient in some of the perturbations.</p>},
  author       = {Olsson, Martin A. and García-Sosa, Alfonso T. and Ryde, Ulf},
  issn         = {0920-654X},
  keyword      = {Bennett acceptance ratio,Charge transformations,D3R Grand Challenge 2016,Docking,Drug design data resource,Free-energy perturbation,Ligand binding,Periodic boundary conditions,Quantum-polarised ligand docking},
  language     = {eng},
  number       = {1},
  pages        = {211--224},
  publisher    = {Kluwer},
  series       = {Journal of Computer-Aided Molecular Design},
  title        = {Binding affinities of the farnesoid X receptor in the D3R Grand Challenge 2 estimated by free-energy perturbation and docking},
  url          = {http://dx.doi.org/10.1007/s10822-017-0056-z},
  volume       = {32},
  year         = {2018},
}