Computational Approaches to Lipophilicity: Methods and Applications

Carrupt, Pierre‐Alain; Testa, Bernard; Gaillard, Patrick

doi:10.1002/9780470125885.ch5

Cited by 70 publications

(20 citation statements)

References 178 publications

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“…In these models the solute is usually considered at all-atom level or using various molecular and fragmental descriptors 26 , while solvent is treated implicitly as an isotropic liquid phase. However, these models are usually employed for small molecules that are fully exposed to the solvent, but not to macromolecules that have a significant fraction of solvent-inaccessible atoms.…”

Section: Introductionmentioning

confidence: 99%

Anisotropic Solvent Model of the Lipid Bilayer. 1. Parameterization of Long-Range Electrostatics and First Solvation Shell Effects

Lomize

Pogozheva

Mosberg

2011

J. Chem. Inf. Model.

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A new implicit solvation model was developed for calculating free energies of transfer of molecules from water to any solvent with defined bulk properties. The transfer energy was calculated as a sum of the first solvation shell energy and the long-range electrostatic contribution. The first term was proportional to solvent accessible surface area and solvation parameters (σi) for different atom types. The electrostatic term was computed as a product of group dipole moments and dipolar solvation parameter (η) for neutral molecules, or using a modified Born equation for ions. The regression coefficients in linear dependencies of solvation parameters σi and η on dielectric constant, solvatochromic polarizability parameter π*, and hydrogen-bonding donor and acceptor capacities of solvents were optimized using 1269 experimental transfer energies from 19 organic solvents to water. The root-mean-square errors for neutral compounds and ions were 0.82 and 1.61 kcal/mol, respectively. Quantification of energy components demonstrates the dominant roles of hydrophobic effect for non-polar atoms and of hydrogen-bonding for polar atoms. The estimated first solvation shell energy outweighs the long-range electrostatics for most compounds including ions. The simplicity and computational efficiency of the model allows its application for modeling of macromolecules in anisotropic environments, such as biological membranes.

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Section: Introductionmentioning

confidence: 99%

Anisotropic Solvent Model of the Lipid Bilayer. 1. Parameterization of Long-Range Electrostatics and First Solvation Shell Effects

Lomize

Pogozheva

Mosberg

2011

J. Chem. Inf. Model.

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“…We used the computational software COSMOtherm. The choice of COSMOtherm among a plethora of free and commercial computational tools available today for logP/logD calculations 31 was justified by two reasons: 1) unlike most logP calculators it uses the three dimensional structure of the molecules [32][33][34] and 2) COSMOtherm allows calculation of logP values in non octanol/water systems.…”

Section: Introductionmentioning

confidence: 99%

Integrating Intramolecular Hydrogen Bonding (IMHB) Considerations in Drug Discovery Using ΔlogP As a Tool

et al. 2013

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This study demonstrates that logP oct-tol (difference between logPoctanol and logPtoluene) describes compounds propensity to form intramolecular hydrogen bonds (IMHB) and may be considered a privileged molecular descriptor for use in drug discovery and for prediction of IMHB in drug candidates.We identified experimental protocols for acquiring reliable logP oct-tol values on a set of compounds representing IMHB motifs most prevalent in Medicinal Chemistry, mainly molecules capable of forming 6-, 7-member IMHB rings.Furthermore, computational logP oct-tol values obtained with COSMO-RS software provided a good estimate of experimental results and can be used prospectively to assess IMHB.The proposed interpretation method based on logP oct-tol data allowed categorization of the compounds into 2 groups -with high propensity to form IMHB and poor propensity or poor relevance of IMHB.The relative 1 H NMR chemical shift of an exchangeable proton was used to verify presence of IMHB and to validate the IMHB interpretation scheme.4

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“…Particular attention is being paid to dipole moment and lipophilicity as calculated by the MLP (Molecular Lipophilicity Potential) [19]. These two properties vary over a broad range within the conformational space of acetylcholine, and they were highly intercorrelated in each MD simulation.…”

Section: ) Biological Responsesmentioning

confidence: 99%

Musings on ADME Predictions and Structure-Activity Relations

Testa

Vistoli

Pedretti

2005

C&B

Self Cite

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The first part of the paper examines Structure-Activity Relations (SARs) and their components from a very general point of view. The various types of interpretation emerging from statistically valid relations will be examined, namely causal (mechanistic), contextual (empirical), fortuitous, and tautological correlations. Implications for ADME predictions will be seen when discussing the diversity of interactions between active compounds (e.g., drugs) and biological systems. The second part of the paper is more specific and presents the concept of molecular-property space, an all but neglected concept in SARs. Recent results from Molecular Dynamics (MD) simulations and Molecular Interaction Fields (MIF) computations of acetylcholine will be used to illustrate not only the well-known conformational space of this molecule, but also its property space as exemplified by its lipophilicity space. It will be seen that a molecule as small as acetylcholine is able to span a relatively broad property space. Most significantly in an ADME perspective, the molecule is able, within the limits of its property space, to adapt to the medium. This is equivalent to saying that the medium constrains the molecule to resemble it as much as feasible.

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Computational Approaches to Lipophilicity: Methods and Applications

Cited by 70 publications

References 178 publications

Anisotropic Solvent Model of the Lipid Bilayer. 1. Parameterization of Long-Range Electrostatics and First Solvation Shell Effects

Anisotropic Solvent Model of the Lipid Bilayer. 1. Parameterization of Long-Range Electrostatics and First Solvation Shell Effects

Integrating Intramolecular Hydrogen Bonding (IMHB) Considerations in Drug Discovery Using ΔlogP As a Tool

Musings on ADME Predictions and Structure-Activity Relations

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