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.
(Less)
- author
- Olsson, Martin A.
LU
; García-Sosa, Alfonso T.
and Ryde, Ulf
LU
- organization
- publishing date
- 2018-01
- 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
- Springer
- external identifiers
-
- scopus:85028805060
- pmid:28879536
- 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
- 2024-03-31 17:11:09
@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}},
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}},
language = {{eng}},
number = {{1}},
pages = {{211--224}},
publisher = {{Springer}},
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}},
doi = {{10.1007/s10822-017-0056-z}},
volume = {{32}},
year = {{2018}},
}