Patrick Gaillard

Molecular Lipophilicity Potential, a tool in 3D QSAR: Method and applications

SummaryA new method is presented to calculate the Molecular Lipophilicity Potential (MLP). The method is validated by showing that the MLP thus generated on the solvent-accessible surface can be used to back-calculate log P. Because the MLP is shown to be sensitive to conformational effects, the MLP/log P relation is best sought by taking all conformers into account. The MLP method presented here can be used as a third field in CoMFA studies, as illustrated with two series of α1 ligands. In the first series, the steric, electrostatic and lipophilic fields are highly intercorrelated, and taken separately yield comparable models. In the second series of ligands, the best model is obtained with the lipophilic field alone, allowing insights into ligand-receptor interactions.

Structure-Lipophilicity Relationships of Neutral and Protonated β-Blockers, Part I, Intra- and Intermolecular Effects in Isotropic Solvent Systems

The objectives of this study were to validate new experimental techniques used to measure the log P of protonated drugs, and to investigate the inter- and intramolecular forces influencing the partitioning behavior of β-blockers in isotropic biphasic solvent systems. The lipophilicity parameters of a number of β-blockers were measured by two-phase titration, centrifugal partition chromatography (CPC), and cyclic voltammetry (CV) in one or more of the following solvent systems: octanol/water, 1,2-dichloroethane/water, and dibutyl ether/water. CV proved to be a promising technique for measuring the lipophilicity of protonated β-blockers. Derived parameters such as Δlog P (difference between log P in two different solvent systems, a parameter valid for a given solute in a given electrical form) and diff (difference between log P of two different electrical forms of a given solute, in the same system) yielded insights into inter- and intramolecular interactions characteristic of β-blockers. The relevance of these parameters in structure-permeation relationships is explored.

E-STATE FIELDS : APPLICATIONS TO 3D QSAR

SummaryThe derivation of a new 3D QSAR field based on the electrotopological state (E-state) formalism is described. A complementary index and its associated field, the HE-state, describing the polarity of hydrogens is also defined. These new fields are constructed from a nonempirical index that incorporates electronegativity, the inductive influence of neighboring atoms, and the topological state into a single atomistic descriptor. The classic CoMFA steroid test data set was examined with models incorporating the E-state and HE-state fields alone and in combination with steric, electrostatic and hydropathic fields. The single best model was the E-state/HE-state combination with q2=0.803 (three components) and r2=0.979. Using the E-state and/or HE-state fields with other fields consistently produced models with improved statistics, where the E-state fields provided a significant, if not dominant, contribution.

Natural and synthetic xanthones as monoamine oxidase inhibitors: Biological assay and 3D-QSAR

Fifty-nine xanthones (= 9H-xanthen-9-ones) of natural or synthetic origin were investigated for their inhibitory activity toward monoamine-oxidase A (MAO-A) and MAO-B. The compounds demonstrated reversible. time-independent activities, with selectivity toward MAO-A. The most active inhibitor had an IC50 of 40 nM. Electron absorption spectroscopy revealed the formation of a 1:1 charge-transfer complex between lumiflavine and xanthones. 3D-QSAR Studies according to the CoMFA/GOLPE procedure provided information on the relationship between steric and electrostatic fields and MAO-A inhibition. The ALMOND procedure yielded additional topographical information on structural factors favoring activity

Intermolecular Forces Expressed in 1,2-Dichloroethane/Water Partition Coefficients: A Solvatochromic Analysis

Reference LEPA-ARTICLE-1997-010doi:10.1039/a606374hView record in Web of Science Record created on 2005-11-07, modified on 2017-05-12

Inhibition of monoamine oxidase by isoquinoline derivatives: Qualitative and 3D-quantitative structure-activity relationships

A series of isoquinolines, N-methyl-1,2-dihydroisoquinolines, N-methyl-1,2,3,4-tetrahydroisoquinolines, 1,2,3,4-tetrahydroisoquinolines, and N-methylisoquinolinium ions were tested as inhibitors of monoamine oxidases A and B. All compounds were found to act as reversible and time-independent MAO inhibitors, often with a distinct selectivity towards MAO-A. As a class, the N-methylisoquinolinium ions were found to be the most active MAO-A inhibitors, with N-methyl-6-methoxyisoquinolinium ion emerging as a potent (IC50 = 0.81 microM) and competitive MAO-A inhibitor. Comparative molecular field analysis (CoMFA, a 3D-QSAR method) of MAO-A inhibition was performed using the data reported here and in the literature. Using the steric and lipophilic fields of the inhibitors, quantitative models with reasonable predictive power were obtained that point to the importance of steric, lipophilic, and polar interactions in modulating MAO-A inhibitory activity.

The conformation-dependent lipophilicity of morphine glucuronides as calculated from their molecular lipophilicity potential

Abstract A whole range of conformers of morphine-6-O-glucuronide and morphine 3-O-glucuronide were examined for their theoretical log P values using the molecular lipophilicity potential method. The results substantiate the “chameleonic” behavior of morphine glucuronides to exist in water as hydrophilic, extended conformers, and in lipidic media as folded, more lipophilic conformers.

Development of molecular hydrogen-bonding potentials (MHBPs) and their application to structure–permeation relations

Hydrogen bonds are major forces of recognition in biochemistry and molecular pharmacology; they are an essential component of intermolecular interactions and determine to a significant extent the 3D-structure of bio-macromolecules. To explore three-dimensional H-bonding properties, a new tool called Molecular Hydrogen-Bonding Potentials (MHBPs) was created. The development of this tool is based on a stepwise procedure similar to the one used successfully to generate the Molecular Lipophilicity Potential (MLP). First, a H-bonding fragmental system was developed starting from published solvatochromic parameters. An atomic H-bonding donor fragmental value (alpha) is associated to each hydrogen atom in a polar moiety. Similarly, an atomic H-bonding acceptor fragmental value (beta) is associated to each polar atom. A distance function and an angle function were defined to take into account variations of the MHBPs in space. The fragmental system and the geometric functions were then combined to generate the MHBPs. These are calculated at each point of an adequate molecular surface or on a three-dimensional grid. The MHBPs were compared with GRID interactions energies and correlated with success to oral drug absorption data. Available examples demonstrate that the MHBPs are a promising computational tool in drug design. Their combination with CoMFA and VolSurf is being studied.

Solvatochromic analysis of di-n-butyl ether/water partition coefficients as compared to other solvent systems

In order to assess the molecular parameters controlling partition coefficients in the di-n-butyl ether/water system, a set of 43 solutes has been selected. Centrifugal partition chromatography and the pH-metric method have been used to measure log Pdbe values. Using linear solvation Gibbs-energy relationship analyses, the balance of intermolecular forces governing the di-n-butyl ether partition coefficient has been identified, indicating that the partitioning of H-bond acceptors is less important in the di-n-butyl ether/water system than in the n-octanol/water system. The di-n-butyl ether/water system appears to be a valuable substitute to propyleneglycol dipelargolate/water in the detailed characterisation of intermolecular interactions of complex compounds using the ‘critical quarter’ methodology.

Stabilization of the hydrophilic sphere of iobitridol, an iodinated contrast agent, as revealed by experimental and computational investigations

AbstractPurpose. The regular distribution in space and the stability in time of the hydrophilic sphere surrounding iobitridol were investigated. This is a novel yet important concept in the design of polyiodinated contrast agents since such a sphere is meant to hide their hydrophobic core and thus prevent hydrophobic interactions with biomacromolecules and hence chemotoxicity. Methods. The methods used were experimental (HPLC, 1H- and 13C-NMR spectroscopy) and computational (calculation of conformational behavior and molecular electrostatic potentials). Results. lobitridol exists as a mixture of stereoisomers due to hindered rotation around several bonds. High-temperature molecular dynamics established the existence between 0 and 15 kcal/mol of 238 conformers belonging to 14 classes. Most of these conformers have an inaccessible hydrophobic core, and variable temperature molecular dynamics confirmed that the hydrophilic sphere around iobitridol is stable against external disruption. Conclusions. This study has demonstrated that iobitridol fulfills the physicochemical and structural criteria believed to render a polyiodinated contrast agent inert toward interacting with biomacromolecules.