Luc Morin-Allory

2D QSAR Consensus Prediction for High-Throughput Virtual Screening. An Application to COX-2 Inhibition Modeling and Screening of the NCI Database

Using classification (SOM, LVQ, Binary, Decision Tree) and regression algorithms (PLS, BRANN, k-NN, Linear), this paper details the building of eight 2D-QSAR models from a 266 COX-2 inhibitor training set. The predictive performances of these eight models were subsequently compared using an 88 COX-2 inhibitor test set. Each ligand is described by 52 2D descriptors expressed as van der Waals Surface Areas (P_VSA) and its COX-2 binding IC50. One of our best predictive models is the neural network model (BRANN), which is able to select a subset, from the 88 ligand test set, that contains 94% COX-2 active inhibitors (pIC50>7.5) and detects 71% of all the actives. We then introduce a QSAR consensus prediction protocol that is shown to be more predictive than any single QSAR model: our C3 consensus approach is able to select a subset from the 88 ligand test set that contains 94% active inhibitors and 83% of all the actives. The 2D QSAR consensus protocol was finally applied to the high-throughput virtual screening of the NCI database, containing 193,477 organic compounds.

Champs d'application d'un nouveau détecteur évaporatif á diffusion de lumière pour la chromatographie liquide hautes performances et la chromatographie en phase supercritique☆

Abstract Application fields of a new evaporative light scattering detector for high-performance liquid chromatography and supercritical fluid chromatography New application capabilities of detection using the measurement of light scattered by microparticles are shown. They are realized with a new evaporative light scattering detector which is (i) compatible with low volatile eluents; no degradation of thermal sensitive compounds is observed; (ii) compatible with supercritical fluid chromatography. These additonal advantages justify the development of new light scattering detectors that can also be used to the stability control of chromatographic systems.

Managing, profiling and analyzing a library of 2.6 million compounds gathered from 32 chemical providers

SummaryThe data for 3.8 million compounds from structural databases of 32 providers were gathered and stored in a single chemical database. Duplicates are removed using the IUPAC International Chemical Identifier. After this, 2.6 million compounds remain. Each database and the final one were studied in term of uniqueness, diversity, frameworks, ‘drug-like’ and ‘lead–like’ properties. This study also shows that there are more than 87 000 frameworks in the database. It contains 2.1 million ‘drug-like’ molecules among which, more than one million are ‘lead-like’. This study has been carried out using ‘ScreeningAssistant’, a software dedicated to chemical databases management and screening sets generation. Compounds are stored in a MySQL database and all the operations on this database are carried out by Java code. The druglikeness and leadlikeness are estimated with ‘in–house’ scores using functions to estimate convenience to properties; unicity using the InChI code and diversity using molecular frameworks and fingerprints. The software has been conceived in order to facilitate the update of the database. ‘ScreeningAssistant’ is freely available under the GPL license.

High performance liquid chromatography of raw sugars and polyols using bonded silica gels

SummaryBonded silica columns have been evaluated for their ability to separate carbohydrates and polyols. Mobile phases consisting of dichloromethane/methanol produced the best separations in comparison with the acetonitrile/water mixtures commonly used with amino columns. Of all the bonded phases tested, LiChrospher Diol silica provided the best separations, and selectivities were not very different from those obtained on the most popular system using an amino bonded phase and acetonitrile/water as eluent. In addition, diol columns with a dichloromethane/methanol eluent offer excellent stability with no Schiff’s base formation of reducing sugars. Using an evaporative light scattering detector, low limit detection is obtainable (20 ng of glucose from a column) and gradient elution is quite feasible.

Insights into chiral recognition mechanisms in supercritical fluid chromatography. II. Factors contributing to enantiomer separation on tris-(3,5-dimethylphenylcarbamate) of amylose and cellulose stationary phases

In this second part of our work on enantioselective supercritical fluid chromatography (SFC), we investigate the factors participating in the chiral recognition process on tris-(3,5-dimethylphenylcarbamate) of amylose and cellulose chiral stationary phases (CSPs). 135 racemates with diverse structures were analysed under identical SFC conditions on both stationary phases. The possibility of identifying the differential interactions of an enantiomer pair within the chromatographic system is assessed using a modified version of the solvation parameter model and factorial discriminant analysis. It is illustrated that one relationship of intermolecular interactions is insufficient to express the enantioseparation of different groups of racemates. An innovative approach is used in unravelling the interactions taking part in the enantiorecognition process. Different intermolecular interactions participating in the enantiomeric separation are demonstrated between the two stationary phases.

Controle de certains systemes de chromatographie liquide haute performance à láide d'un détecteur évaporatif à diffusion de lumière

Abstract The quasi universal character of the light scattering detection of microparticles permits in the case of sugar analysis to choose the column and to control its evolution as a function of time. A simple test is proposed to induce the beginning of the regeneration of resinous CA2+. LiChrosorb Diol support is preferred to aminopropyl silica to realize at the same time a gradient elution and a good sensitivity (30–50 ng).

Factor analysis and experiment design in high-performance liquid chromatography : VII. Classification of 23 reversed-phase high-performance liquid chromatographic packings and identification of factors governing selectivity

Abstract The chromatographic behaviour of 63 solutes was investigated in reversed- phase high-performance liquid chromatographic (RP-HPLC) systems with the same mobil phase and 23 different commercially available packings. The results provide a new insight into variations of selectivity with column type. The factors affecting solute selectivity in RP-HPLC systems, emerging from correspondence factor analysis (CFA), are grouped into types: hydrophobic factor and chemical and/or steric factors. The relative importance of these factors is considered. Physical and chemical properties of packings, expected to affect the solute selectivity, such as the nature of the organic ligand, carbon loading, end-capping procedure, shape of silica, monomeric or polymeric layer and compression technique, are compared. It is shown that only the three first influence the selectivity. The CFA results also permit a classification of the packings on a relative scale of “hydophobicity”. To position any ne RP-HPLC packing on this scale and to estimate its “hydrophobicity”, a test with sets of only four or five test compounds is proposed.

Visual characterization and diversity quantification of chemical libraries: 1. creation of delimited reference chemical subspaces.

High-throughput screening (HTS) is a well-established technology which can test up to several million compounds in a few weeks. Despite these appealing capabilities, available resources and high costs may limit the number of molecules screened, making diversity analysis a method of choice to design and prioritize screening libraries. With a constantly increasing number of molecules available for screening, chemical space has become a key concept for visualizing, analyzing, and comparing chemical libraries. In this first article, we present a new method to build delimited reference chemical subspaces (DRCS). A set of 16 million screening compounds from 73 chemical providers has been gathered, resulting in a database of 6.63 million standardized and unique molecules. These molecules have been used to create three DRCS using three different sets of chemical descriptors. A robust principal component analysis model for each space has been obtained, whereby molecules are projected in a reduced two-dimensional viewable space. The specificity of our approach is that each reduced space has been delimited by a representative contour encompassing a very large proportion of molecules and reflecting its overall shape. The methodology is illustrated by mapping and comparing various chemical libraries. Several tools used in these studies are made freely available, thus enabling any user to compute DRCS matching specific requirements.

Factor analysis and experiment design in high-performance liquid chromatography. VI: Comparison of the retention mechanism for fourteen octadecylsilica packings

Abstract The selectivity of 63 compounds on 14 ODS packings for reversed-phase high-performance liquid chromatography has been studied. Plots of logarithmic retention factors, log k′, measured on column pairs with the same mobile phase, are used to compare the energetics of retention and to study the similarity of the retention mechanisms on all the possible pairs of packings. To discuss the specific properties of the packings, a new criterion of the similarity of retention mechanism is proposed. The chi-squared (χ2) distance can be used to describe the deviation from proportionality between the capacity factors measured on the column pairs. Correspondence factor analysis (CFA) gives access to the χ2 distance in the reduced space of the main factors affecting solute selectivity. Additionally, the relative importance of the “hydrophobic” and non-hydrophobic effects can be estimated. The extracted factors allow the ajj′ parameters to be recreated, i.e., the ratio of the Gibbs free energy for the Jth and J′th phase pair.

Analysis of sugars by supercritical fluid chromatography using polar packed columns and light-scattering detection

Abstract The application of supercritical fluid chromatography (SFC) with polar packed columns and light-scattering detection for the analysis of sugars is reported. Cyano-, diol- and nitro-bonded silicas were used with carbon dioxide-methanol mobile phases and a comparison of sugar retention was carried out. These SFC systems showed different selectivites from that found in high-performance liquid chromatography. The association of a constant flow-rate of carbon dioxide and a variable flow-rate of methanol affords the elution of mono-, di- and trisaccharides in the same analysis without baseline drift.