Identification of New Nonsteroidal RORα Ligands; Related Structure-Activity Relationships and Docking Studies.

A high throughput screen was developed to identify novel, nonsteroidal RORα agonists. Among the validated hit compounds, the 4-(4-(benzyloxy)phenyl)-5-carbonyl-2-oxo-1,2,3,4-tetrahydropyrimidine scaffold was the most prominent. Among the numerous analogues tested, compounds 8 and 9 showed the highest activity.

Mining collections of compounds with Screening Assistant 2.

Background: High-throughput screening assays have become the starting point of many drug discovery programs for large pharmaceutical companies as well as academic organisations. Despite the increasing throughput of screening technologies, the almost infinite chemical space remains out of reach, calling for tools dedicated to the analysis and selection of the compound collections intended to be screened.

Results: We present Screening Assistant 2 (SA2), an open-source JAVA software dedicated to the storage and analysis of small to very large chemical libraries.

Visual characterization and diversity quantification of chemical libraries: 2. Analysis and selection of size-independent, subspace-specific diversity indices.

High Throughput Screening (HTS) is a standard technique widely used to find hit compounds in drug discovery projects. The high costs associated with such experiments have highlighted the need to carefully design screening libraries in order to avoid wasting resources. Molecular diversity is an established concept that has been used to this end for many years.

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.

Synthesis and structure-activity relationships of constrained heterocyclic analogues of combretastatin A4.

A series of combretastatin A4 (CA4) analogues with a lactam or lactone ring fused to the trimethoxyphenyl or the B-phenyl moiety were synthesized in an efficient and stereoselective manner by using a domino Heck-Suzuki-Miyaura coupling reaction. The vascular-disrupting potential of these conformationally restricted CA4 analogues was assessed by various in vitro assays: inhibition of tubulin polymerization, modification of endothelial cell morphology, and disruption of endothelial cell cords. Compounds were also evaluated for their growth inhibitory effects against murine and human tumor cells.

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.

Insights into chiral recognition mechanisms in supercritical fluid chromatography. I. Non-enantiospecific interactions contributing to the retention on tris-(3,5-dimethylphenylcarbamate) amylose and cellulose stationary phases.

In this series of papers, we use a systematic approach to investigate the factors responsible for enantio-recognition in supercritical fluid chromatography (SFC) on chiral stationary phases (CSPs). In this first part, the interactions contributing to the retentions of the achiral solutes are measured with a modified version of the solvation parameter model. Since stereospecific interactions were not accounted for in the classical linear solvation energy relationship using Abraham descriptors, we introduce two additional descriptors, flexibility and globularity, to rationally quantify the stereochemical properties that may significantly affect enantiomeric resolutions.

Synthesis and biological evaluation of cis-locked vinylogous combretastatin-A4 analogues: derivatives with a cyclopropyl-vinyl or a cyclopropyl-amide bridge.

A series of novel combretastatin A4 analogues, in which the cis-olefinic bridge is replaced by a cyclopropyl-vinyl or a cyclopropyl-amide moiety, were synthesized and evaluated for inhibition of tubulin polymerization and antiproliferative activity. The derivative 9a with a (cis,E)-cyclopropyl-vinyl unit is the most promising compound. As expected, molecular docking of 9a has shown that only one of the cis-cyclopropyl enantiomers is a good ligand for tubulin.

Reverse pharmacognosy: identifying biological properties for plants by means of their molecule constituents: application to meranzin.

Reverse pharmacognosy aims at finding biological targets for natural compounds by virtual or real screening and identifying natural resources that contain the active molecules. We report herein a study focused on the identification of biological properties of meranzin, a major component isolated from Limnocitrus littoralis (Miq.) Swingle.

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

The 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.

Optimization and validation of a docking-scoring protocol; application to virtual screening for COX-2 inhibitors.

To exploit available structural information about the cyclooxygenase enzyme for the virtual screening of large chemical libraries, a docking-scoring protocol was tuned and validated. The screening accuracy was assessed using a series of known inhibitors and a set of diverse a priori inactive compounds that was seeded with known active ligands. The major parameters of the DOCK algorithm were investigated.

Rapid analysis of triterpenic acids by liquid chromatography using porous graphitic carbon and evaporative light scattering detection.

An original system which uses Porous Graphitic Carbon as support and a mixture of organic solvents as mobile phase is proposed for the analysis of triterpenic acids by liquid chromatography. The separation of betulinic acid, ursolic acid, oleanolic acid, and 18alpha- and 18beta-glycyrrhetinic acids was carried out within a short time and monitored by evaporative light scattering detection as universal detection method. Molecular modelling studies show that the main contribution to the selectivity comes from the electrostatic interaction characterised by the dipole moment of the products.

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.

Structure and thermodynamics of alpha-, beta-, and gamma-cyclodextrin dimers. Molecular dynamics studies of the solvent effect and free binding energies.

The alpha-, beta-, and gamma-cyclodextrin (CyDs) dimers were studied by molecular dynamics (MD) simulations in water as an explicit solvent. The relative stability of dimers and the involved molecular interactions were determined. Three possible starting orientations were considered for the dimers: head-to-head, head-to-tail, and tail-to-tail.