How accurate are continuum solvation models for druglike molecules?
(2009) In Journal of ComputerAided Molecular Design 23(7). p.395409 Abstract
 We have estimated the hydration free energy for 20 neutral druglike molecules, as well as for three series of 611 inhibitors to avidin, factor Xa, and galectin3 with four different continuum solvent approaches (the polarised continuum method the Langevin dipole method, the finitedifference 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 16 kJ/mol for neutral molecules and 430 kJ/mol for ions. However, for the druglike molecules, the accuracy seems to be appreciably worse. The reason for... (More)
 We have estimated the hydration free energy for 20 neutral druglike molecules, as well as for three series of 611 inhibitors to avidin, factor Xa, and galectin3 with four different continuum solvent approaches (the polarised continuum method the Langevin dipole method, the finitedifference 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 16 kJ/mol for neutral molecules and 430 kJ/mol for ions. However, for the druglike molecules, the accuracy seems to be appreciably worse. The reason for this is that druglike 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 220 kJ/mol absolute error for the druglike molecules in this investigation, or 23,000 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 25 kJ/mol (corresponding to an uncertainty of a factor of 27 in the binding constant). Interestingly, the generalised Born methods typically give better results than the PoisonBoltzmann methods. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1441652
 author
 Kongsted, Jacob ; Söderhjelm, Pär ^{LU} and Ryde, Ulf ^{LU}
 organization
 publishing date
 2009
 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 ComputerAided Molecular Design
 volume
 23
 issue
 7
 pages
 395  409
 publisher
 Kluwer
 external identifiers

 wos:000267222300002
 pmid:19444622
 scopus:84962366080
 ISSN
 15734951
 DOI
 10.1007/s1082200992716
 language
 English
 LU publication?
 yes
 additional info
 The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Theoretical Chemistry (S) (011001039)
 id
 0f5b5d759dc64833851814bae5bc0cc0 (old id 1441652)
 date added to LUP
 20160401 13:28:45
 date last changed
 20200506 02:57:31
@article{0f5b5d759dc64833851814bae5bc0cc0, abstract = {We have estimated the hydration free energy for 20 neutral druglike molecules, as well as for three series of 611 inhibitors to avidin, factor Xa, and galectin3 with four different continuum solvent approaches (the polarised continuum method the Langevin dipole method, the finitedifference 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 16 kJ/mol for neutral molecules and 430 kJ/mol for ions. However, for the druglike molecules, the accuracy seems to be appreciably worse. The reason for this is that druglike 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 220 kJ/mol absolute error for the druglike molecules in this investigation, or 23,000 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 25 kJ/mol (corresponding to an uncertainty of a factor of 27 in the binding constant). Interestingly, the generalised Born methods typically give better results than the PoisonBoltzmann methods.}, author = {Kongsted, Jacob and Söderhjelm, Pär and Ryde, Ulf}, issn = {15734951}, language = {eng}, number = {7}, pages = {395409}, publisher = {Kluwer}, series = {Journal of ComputerAided Molecular Design}, title = {How accurate are continuum solvation models for druglike molecules?}, url = {http://dx.doi.org/10.1007/s1082200992716}, doi = {10.1007/s1082200992716}, volume = {23}, year = {2009}, }