Cargando…

The SAMPL5 challenge for embedded-cluster integral equation theory: solvation free energies, aqueous p$K_a$, and cyclohexane–water log D

We predict cyclohexane–water distribution coefficients (log D7.4) for drug-like molecules taken from the SAMPL5 blind prediction challenge by the “embedded cluster reference interaction site model” (EC-RISM) integral equation theory. This task involves the coupled problem of predicting both partitio...

Descripción completa

Detalles Bibliográficos
Autores principales: Tielker, Nicolas, Tomazic, Daniel, Heil, Jochen, Kloss, Thomas, Ehrhart, Sebastian, Güssregen, Stefan, Schmidt, K. Friedemann, Kast, Stefan M.
Lenguaje:eng
Publicado: 2016
Materias:
Acceso en línea:https://dx.doi.org/10.1007/s10822-016-9939-7
http://cds.cern.ch/record/2258358
_version_ 1780953843860766720
author Tielker, Nicolas
Tomazic, Daniel
Heil, Jochen
Kloss, Thomas
Ehrhart, Sebastian
Güssregen, Stefan
Schmidt, K. Friedemann
Kast, Stefan M.
author_facet Tielker, Nicolas
Tomazic, Daniel
Heil, Jochen
Kloss, Thomas
Ehrhart, Sebastian
Güssregen, Stefan
Schmidt, K. Friedemann
Kast, Stefan M.
author_sort Tielker, Nicolas
collection CERN
description We predict cyclohexane–water distribution coefficients (log D7.4) for drug-like molecules taken from the SAMPL5 blind prediction challenge by the “embedded cluster reference interaction site model” (EC-RISM) integral equation theory. This task involves the coupled problem of predicting both partition coefficients (log P) of neutral species between the solvents and aqueous acidity constants (pKa) in order to account for a change of protonation states. The first issue is addressed by calibrating an EC-RISM-based model for solvation free energies derived from the “Minnesota Solvation Database” (MNSOL) for both water and cyclohexane utilizing a correction based on the partial molar volume, yielding a root mean square error (RMSE) of 2.4 kcal mol−1 for water and 0.8–0.9 kcal mol−1 for cyclohexane depending on the parametrization. The second one is treated by employing on one hand an empirical pKa model (MoKa) and, on the other hand, an EC-RISM-derived regression of published acidity constants (RMSE of 1.5 for a single model covering acids and bases). In total, at most 8 adjustable parameters are necessary (2–3 for each solvent and two for the pKa) for training solvation and acidity models. Applying the final models to the log D7.4 dataset corresponds to evaluating an independent test set comprising other, composite observables, yielding, for different cyclohexane parametrizations, 2.0–2.1 for the RMSE with the first and 2.2–2.8 with the combined first and second SAMPL5 data set batches. Notably, a pure log P model (assuming neutral species only) performs statistically similarly for these particular compounds. The nature of the approximations and possible perspectives for future developments are discussed.
id cern-2258358
institution Organización Europea para la Investigación Nuclear
language eng
publishDate 2016
record_format invenio
spelling cern-22583582019-09-30T06:29:59Zdoi:10.1007/s10822-016-9939-7http://cds.cern.ch/record/2258358engTielker, NicolasTomazic, DanielHeil, JochenKloss, ThomasEhrhart, SebastianGüssregen, StefanSchmidt, K. FriedemannKast, Stefan M.The SAMPL5 challenge for embedded-cluster integral equation theory: solvation free energies, aqueous p$K_a$, and cyclohexane–water log DChemical Physics and ChemistryWe predict cyclohexane–water distribution coefficients (log D7.4) for drug-like molecules taken from the SAMPL5 blind prediction challenge by the “embedded cluster reference interaction site model” (EC-RISM) integral equation theory. This task involves the coupled problem of predicting both partition coefficients (log P) of neutral species between the solvents and aqueous acidity constants (pKa) in order to account for a change of protonation states. The first issue is addressed by calibrating an EC-RISM-based model for solvation free energies derived from the “Minnesota Solvation Database” (MNSOL) for both water and cyclohexane utilizing a correction based on the partial molar volume, yielding a root mean square error (RMSE) of 2.4 kcal mol−1 for water and 0.8–0.9 kcal mol−1 for cyclohexane depending on the parametrization. The second one is treated by employing on one hand an empirical pKa model (MoKa) and, on the other hand, an EC-RISM-derived regression of published acidity constants (RMSE of 1.5 for a single model covering acids and bases). In total, at most 8 adjustable parameters are necessary (2–3 for each solvent and two for the pKa) for training solvation and acidity models. Applying the final models to the log D7.4 dataset corresponds to evaluating an independent test set comprising other, composite observables, yielding, for different cyclohexane parametrizations, 2.0–2.1 for the RMSE with the first and 2.2–2.8 with the combined first and second SAMPL5 data set batches. Notably, a pure log P model (assuming neutral species only) performs statistically similarly for these particular compounds. The nature of the approximations and possible perspectives for future developments are discussed.oai:cds.cern.ch:22583582016
spellingShingle Chemical Physics and Chemistry
Tielker, Nicolas
Tomazic, Daniel
Heil, Jochen
Kloss, Thomas
Ehrhart, Sebastian
Güssregen, Stefan
Schmidt, K. Friedemann
Kast, Stefan M.
The SAMPL5 challenge for embedded-cluster integral equation theory: solvation free energies, aqueous p$K_a$, and cyclohexane–water log D
title The SAMPL5 challenge for embedded-cluster integral equation theory: solvation free energies, aqueous p$K_a$, and cyclohexane–water log D
title_full The SAMPL5 challenge for embedded-cluster integral equation theory: solvation free energies, aqueous p$K_a$, and cyclohexane–water log D
title_fullStr The SAMPL5 challenge for embedded-cluster integral equation theory: solvation free energies, aqueous p$K_a$, and cyclohexane–water log D
title_full_unstemmed The SAMPL5 challenge for embedded-cluster integral equation theory: solvation free energies, aqueous p$K_a$, and cyclohexane–water log D
title_short The SAMPL5 challenge for embedded-cluster integral equation theory: solvation free energies, aqueous p$K_a$, and cyclohexane–water log D
title_sort sampl5 challenge for embedded-cluster integral equation theory: solvation free energies, aqueous p$k_a$, and cyclohexane–water log d
topic Chemical Physics and Chemistry
url https://dx.doi.org/10.1007/s10822-016-9939-7
http://cds.cern.ch/record/2258358
work_keys_str_mv AT tielkernicolas thesampl5challengeforembeddedclusterintegralequationtheorysolvationfreeenergiesaqueouspkaandcyclohexanewaterlogd
AT tomazicdaniel thesampl5challengeforembeddedclusterintegralequationtheorysolvationfreeenergiesaqueouspkaandcyclohexanewaterlogd
AT heiljochen thesampl5challengeforembeddedclusterintegralequationtheorysolvationfreeenergiesaqueouspkaandcyclohexanewaterlogd
AT klossthomas thesampl5challengeforembeddedclusterintegralequationtheorysolvationfreeenergiesaqueouspkaandcyclohexanewaterlogd
AT ehrhartsebastian thesampl5challengeforembeddedclusterintegralequationtheorysolvationfreeenergiesaqueouspkaandcyclohexanewaterlogd
AT gussregenstefan thesampl5challengeforembeddedclusterintegralequationtheorysolvationfreeenergiesaqueouspkaandcyclohexanewaterlogd
AT schmidtkfriedemann thesampl5challengeforembeddedclusterintegralequationtheorysolvationfreeenergiesaqueouspkaandcyclohexanewaterlogd
AT kaststefanm thesampl5challengeforembeddedclusterintegralequationtheorysolvationfreeenergiesaqueouspkaandcyclohexanewaterlogd
AT tielkernicolas sampl5challengeforembeddedclusterintegralequationtheorysolvationfreeenergiesaqueouspkaandcyclohexanewaterlogd
AT tomazicdaniel sampl5challengeforembeddedclusterintegralequationtheorysolvationfreeenergiesaqueouspkaandcyclohexanewaterlogd
AT heiljochen sampl5challengeforembeddedclusterintegralequationtheorysolvationfreeenergiesaqueouspkaandcyclohexanewaterlogd
AT klossthomas sampl5challengeforembeddedclusterintegralequationtheorysolvationfreeenergiesaqueouspkaandcyclohexanewaterlogd
AT ehrhartsebastian sampl5challengeforembeddedclusterintegralequationtheorysolvationfreeenergiesaqueouspkaandcyclohexanewaterlogd
AT gussregenstefan sampl5challengeforembeddedclusterintegralequationtheorysolvationfreeenergiesaqueouspkaandcyclohexanewaterlogd
AT schmidtkfriedemann sampl5challengeforembeddedclusterintegralequationtheorysolvationfreeenergiesaqueouspkaandcyclohexanewaterlogd
AT kaststefanm sampl5challengeforembeddedclusterintegralequationtheorysolvationfreeenergiesaqueouspkaandcyclohexanewaterlogd