In Silico Prediction of Drug Solubility: 1. Free Energy of Hydration

Westergren, Jan; Lindfors, Lennart; Höglund, Tobias; Lüder, Kai; Nordholm, Sture; Kjellander, Roland

doi:10.1021/jp064220w

Cited by 68 publications

(111 citation statements)

References 47 publications

Supporting

Mentioning

109

Contrasting

Order By: Relevance

“…22,26,[70][71][72] The cavity formation free energy has an opposite sign and is apparently anti-correlated to the van-der-Waals term, which is in turn not completely independent on the electrostatic part of the expression. 73 Furthermore, the change in Lennard-Jones solute-water interaction energy brought by restructuring of the solvent in response to the electrostatic interaction is not properly taken into account in the polar part of the LIE expression. 73 We argue that the D-term (e.g.…”

Section: Modeled a Series Of Esters In A Lipase Frommentioning

confidence: 99%

Improving the LIE Method for Binding Free Energy Calculations of Protein–Ligand Complexes

Miranda

Noskov

Valiente

2015

J. Chem. Inf. Model.

View full text Add to dashboard Cite

In this work, we introduced an improved linear interaction energy (LIE) method parameterization for computations of protein–ligand binding free energies. The protocol, coined LIE-D, builds on the linear relationship between the empirical coefficient γ in the standard LIE scheme and the D parameter, introduced in our work. The D-parameter encompasses the balance (difference) between electrostatic (polar) and van der Waals (nonpolar) energies in protein–ligand complexes. Leave-one-out cross-validation showed that LIE-D reproduced accurately the absolute binding free energies for our training set of protein–ligand complexes (<|error|> = 0.92 kcal/mol, SDerror = 0.66 kcal/mol, R(2) = 0.90, QLOO(2) = 0.89, and sPRESS(LOO) = 1.28 kcal/mol). We also demonstrated LIE-D robustness by predicting accurately the binding free energies for three different protein–ligand systems outside the training data set, where the electrostatic and van der Waals interaction energies were calculated with different force fields.

show abstract

Section: Modeled a Series Of Esters In A Lipase Frommentioning

confidence: 99%

Improving the LIE Method for Binding Free Energy Calculations of Protein–Ligand Complexes

Miranda

Noskov

Valiente

2015

J. Chem. Inf. Model.

View full text Add to dashboard Cite

show abstract

“…This supports the view that an important part of the deviation seen in Figure 7A is due to a "contamination" of the FEP electrostatic component with a positive van der Waals term incurred upon turning off the van der Waals potentials, as previously suggested by others. 60,61 There is little correlation between the total nonpolar components calculated with the LIE and FEP methods ( Figure 7B), due to the aforementioned formal redistribution of contributions and the narrower range of values relative to the electrostatic component.…”

Section: Inclusion Of Internal Energy Termsmentioning

confidence: 99%

Rapid Prediction of Solvation Free Energy. 1. An Extensive Test of Linear Interaction Energy (LIE)

Sulea

Corbeil

Purisima

2010

J. Chem. Theory Comput.

View full text Add to dashboard Cite

Abstract:The present study provides a comprehensive systematic analysis on the applicability of the linear interaction energy (LIE) approximation to the prediction of gas-to-water transfer (hydration) free energy. The study is based on molecular dynamics simulations in explicit solvent for an extensive and diverse hydration data set comprising 564 neutral compounds with measured hydration free energies, including a "traditional" data set and the more challenging drug-like SAMPL1 data set. A highly correlative LIE model was achieved without empirical scaling of the solute-solvent interaction energy terms along with a cavity term calibrated to the experiment. This model was particularly accurate for the "traditional" data set and of acceptable accuracy for the SAMPL1 data set, with mean-unsigned-errors below 1 kcal/mol and slightly above 2 kcal/mol, respectively. We have analyzed the sensitivity of the LIE model to several parameters such as continuum correction terms applied outside the explicit water shell, the impact of various charging methods, the applicability of single-conformer representation of the solute, and the inclusion of internal energy terms. The parameters with the greatest sensitivity are the charging methods used, with AM1BCC-SP (without AM1 geometry optimization) charges favored over AM1BCC-OPT and RESP charges. The inclusion of the change in intramolecular van der Waals and electrostatic energies between the solution and gas phases can also lead to improved prediction accuracies. Functional group based error analysis identified several chemical classes as minor outliers with systematic errors. A direct comparison of the LIE and free energy perturbation (FEP) approaches using the same force field and charging method shows that the LIE approximation is at least as accurate as the FEP approach with a reduction of computing time by at least 1 order of magnitude.

show abstract

“…[1,3] In some thermodynamic cycles, the free energy of hydration (DG hyd ) has to be determined accurately to predict ligand binding affinities. [4] Further, DG hyd is important for drugs' solubility [5] and their partitioning between between phases, usually water and n-octanol are used in experimental studies of drug cell permeation. The latter is often used as a model of the cell membrane in experimental studies with so-called log P values.…”

Section: Introductionmentioning

confidence: 99%

Partial atomic charges and their impact on the free energy of solvation

et al. 2012

View full text Add to dashboard Cite

Free energies of solvation (ΔG) in water and n-octanol have been computed for common drug molecules by molecular dynamics simulations with an additive fixed-charge force field. The impact of the electrostatic interactions was investigated by computing the partial atomic charges with four methods that all fit the charges from the quantum mechanically determined electrostatic potential (ESP). Due to the redistribution of electron density that occurs when molecules are transferred from gas phase to condensed phase, the polarization impact was also investigated. By computing the partial atomic charges with the solutes placed in a conductor-like continuum, the charges were effectively polarized to take the polarization effects into account. No polarization correction term or similar was considered, only the partial atomic charges. Results show that free energies are very sensitive to the choice of atomic charges and that ΔG can differ by several k(B)T depending on the charge computing method. Inclusion of polarization effects makes the solutes too hydrophilic with most methods and in vacuo charges make the solutes too hydrophobic. The restrained-ESP methods together with effectively polarized charges perform well in our test set and also when applied to a larger set of molecules. The effect of water models is also highlighted and shows that the conclusions drawn are valid for different three-point models. Partitioning between an aqueous and a hydrophobic phase is also described better if the two environment's polarization is taken into account, but again the results are sensitive to the charge calculation method. Overall, the results presented here show that effectively polarized charges can improve the description of solvating a drug-like molecule in a solvent and that the choice of partial atomic charges is crucial to ensure that molecular simulations produce reliable results.

show abstract

In Silico Prediction of Drug Solubility: 1. Free Energy of Hydration

Cited by 68 publications

References 47 publications

Improving the LIE Method for Binding Free Energy Calculations of Protein–Ligand Complexes

Improving the LIE Method for Binding Free Energy Calculations of Protein–Ligand Complexes

Rapid Prediction of Solvation Free Energy. 1. An Extensive Test of Linear Interaction Energy (LIE)

Partial atomic charges and their impact on the free energy of solvation

Contact Info

Product

Resources

About