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How accurate are continuum solvation models for drug-like molecules?

Kongsted, Jacob; Söderhjelm, Pär LU and Ryde, Ulf LU (2009) In Journal of Computer-Aided Molecular Design 23(7). p.395-409
Abstract
We have estimated the hydration free energy for 20 neutral drug-like molecules, as well as for three series of 6-11 inhibitors to avidin, factor Xa, and galectin-3 with four different continuum solvent approaches (the polarised continuum method the Langevin dipole method, the finite-difference solution of the Poisson equation, and the generalised Born method), and several variants of each, giving in total 24 different methods. All four types of methods have been thoroughly calibrated for a number of experimentally known small organic molecules with a mean absolute deviation (MAD) of 1-6 kJ/mol for neutral molecules and 4-30 kJ/mol for ions. However, for the drug-like molecules, the accuracy seems to be appreciably worse. The reason for... (More)
We have estimated the hydration free energy for 20 neutral drug-like molecules, as well as for three series of 6-11 inhibitors to avidin, factor Xa, and galectin-3 with four different continuum solvent approaches (the polarised continuum method the Langevin dipole method, the finite-difference solution of the Poisson equation, and the generalised Born method), and several variants of each, giving in total 24 different methods. All four types of methods have been thoroughly calibrated for a number of experimentally known small organic molecules with a mean absolute deviation (MAD) of 1-6 kJ/mol for neutral molecules and 4-30 kJ/mol for ions. However, for the drug-like molecules, the accuracy seems to be appreciably worse. The reason for this is that drug-like molecules are more polar than small organic molecules and that the uncertainty of the methods is proportional to the size of the solvation energy. Therefore, the accuracy of continuum solvation methods should be discussed in relative, rather than absolute, terms. In fact, the mean unsigned relative deviations of the best solvation methods, 0.09 for neutral and 0.05 for ionic molecules, correspond to 2-20 kJ/mol absolute error for the drug-like molecules in this investigation, or 2-3,000 in terms of binding constants. Fortunately, the accuracy of all methods can be improved if only relative energies within a series of inhibitors are considered, especially if all of them have the same net charge. Then, all except two methods give MADs of 2-5 kJ/mol (corresponding to an uncertainty of a factor of 2-7 in the binding constant). Interestingly, the generalised Born methods typically give better results than the Poison-Boltzmann methods. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Free energy of hydration, Continuum methods, PCM, Langevin dipoles, Generalised Born, FDPB, Solvation energy
in
Journal of Computer-Aided Molecular Design
volume
23
issue
7
pages
395 - 409
publisher
Kluwer
external identifiers
  • wos:000267222300002
  • scopus:67649827411
ISSN
1573-4951
DOI
10.1007/s10822-009-9271-6
language
English
LU publication?
yes
id
0f5b5d75-9dc6-4833-8518-14bae5bc0cc0 (old id 1441652)
date added to LUP
2009-07-27 15:45:04
date last changed
2016-09-20 04:29:37
@article{0f5b5d75-9dc6-4833-8518-14bae5bc0cc0,
  abstract     = {We have estimated the hydration free energy for 20 neutral drug-like molecules, as well as for three series of 6-11 inhibitors to avidin, factor Xa, and galectin-3 with four different continuum solvent approaches (the polarised continuum method the Langevin dipole method, the finite-difference solution of the Poisson equation, and the generalised Born method), and several variants of each, giving in total 24 different methods. All four types of methods have been thoroughly calibrated for a number of experimentally known small organic molecules with a mean absolute deviation (MAD) of 1-6 kJ/mol for neutral molecules and 4-30 kJ/mol for ions. However, for the drug-like molecules, the accuracy seems to be appreciably worse. The reason for this is that drug-like molecules are more polar than small organic molecules and that the uncertainty of the methods is proportional to the size of the solvation energy. Therefore, the accuracy of continuum solvation methods should be discussed in relative, rather than absolute, terms. In fact, the mean unsigned relative deviations of the best solvation methods, 0.09 for neutral and 0.05 for ionic molecules, correspond to 2-20 kJ/mol absolute error for the drug-like molecules in this investigation, or 2-3,000 in terms of binding constants. Fortunately, the accuracy of all methods can be improved if only relative energies within a series of inhibitors are considered, especially if all of them have the same net charge. Then, all except two methods give MADs of 2-5 kJ/mol (corresponding to an uncertainty of a factor of 2-7 in the binding constant). Interestingly, the generalised Born methods typically give better results than the Poison-Boltzmann methods.},
  author       = {Kongsted, Jacob and Söderhjelm, Pär and Ryde, Ulf},
  issn         = {1573-4951},
  keyword      = {Free energy of hydration,Continuum methods,PCM,Langevin dipoles,Generalised Born,FDPB,Solvation energy},
  language     = {eng},
  number       = {7},
  pages        = {395--409},
  publisher    = {Kluwer},
  series       = {Journal of Computer-Aided Molecular Design},
  title        = {How accurate are continuum solvation models for drug-like molecules?},
  url          = {http://dx.doi.org/10.1007/s10822-009-9271-6},
  volume       = {23},
  year         = {2009},
}