Biomedical subjects

Claudia Bonaccini

Publications and source records attributed to Claudia Bonaccini.

5 recordsLinked to original sources

PubMed2005

Insight into 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamides as peripheral benzodiazepine receptor ligands: synthesis, biological evaluation and 3D-QSAR investigation.

The present paper reports the synthesis and binding studies of new 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamides as selective Peripheral Benzodiazepine Receptor (PBR) ligands. The variability of substituents at the 3-position was investigated and a 3D-QSAR model was proposed to evaluate the effect of different substitutions on the acetamide moiety. In addition, a subset of the novel compounds showing high affinity for PBR was tested for their ability to modulate the steroid biosynthesis in C6 glioma cells.

Acetamides↗

PubMed2005

Searching for a reliable orientation of ligands in their binding site: comparison between a structure-based (Glide) and a ligand-based (FIGO) approach in the case study of PDE4 inhibitors.

Two 3D QSAR Grid/Golpe models, differing in the alignment criterion of the studied phosphodiesterase 4 (PDE4) inhibitors, were compared. The docking-guided alignment, obtained by exploiting the known 3D structure of the PDE4, was used to test and validate the field-fit alignment solution proposed by FIGO procedure. The analysis of the direct (docking) and indirect (FIGO) superposition methodologies occurs through the comparison of the respective PLS coefficient maps. The inclusion in the FIGO algorithm of factors related to the hydrophobicity and shape of the molecules leads to promising results, making the new FIGO algorithm a valid alternative in the molecule overlay, particularly when the 3D structure of the target is unknown.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2004

GRIND-derived pharmacophore model for a series of alpha-tropanyl derivative ligands of the sigma-2 receptor.

A pharmacophore model for the sigma-2 receptor was derived using GRIND (GRid INdependent Descriptors) descriptors arising from a 3D-level procedure whose main prerogative is that it does not require ligand alignment. PLS models for sigma-2 affinity (sigma-2 model: r2=0.83, q2=0.63) and sigma-1/sigma-2 selectivity (r2=0.72, q2=0.46) were derived using a series of alpha-tropanyl derivatives. The models provide pictures of the virtual receptor site (VRS) significant enough to attain a qualitative pharmacophoric representation of the sigma receptor. They give the internal geometrical relationships within two hydrophobic areas (hydrophobic-1 and -2) and a H-bond donor receptor region with which ligands establish non-covalent bonds.

Computer Simulation↗

PubMed2003

Field interaction and geometrical overlap: a new simplex and experimental design based computational procedure for superposing small ligand molecules.

Alignment of molecules is a crucial and time-consuming step in any 3D-QSAR study. For this reason, the field interaction and geometrical overlap (FIGO) procedure presented in this paper is particularly relevant because it can provide an objective and automatic superposition of ligands through the computation of an appropriate alignment index (AI). Ligand overlay takes place via a simplex optimization of the AI function. Experimental design strategies (full factorial design, D-optimal design) are used to define the starting positions of the superposing molecules. Overlay experiments are carried out to test the performance of the method. Comparison between the results obtained with FIGO and known ligand-receptor X-ray crystallographic data (Protein Data Bank) suggests that FIGO is an effective and reliable computational procedure.

Benzene Derivatives↗

PubMed2003

Synthesis and benzodiazepine receptor affinity of pyrazolo[1,5-a]pyrimidine derivatives. 3. New 6-(3-thienyl) series as alpha 1 selective ligands.

New 3-aryl-6-(3-thienyl)pyrazolo[1,5-a]pyrimidin-7-ones (2a-j) are synthesized and evaluated in vitro on Bz/GABA(A) receptors and on recombinant benzodiazepine receptors (alpha x beta 2/3 gamma 2; x = 1-3, 5) expressed in HEK293 cells. SAR studies on the new compounds are conducted and molecular modeling is accomplished to better investigate requirements leading to subtype selectivity. Some of the synthesized compounds are tested in vivo to explore their pharmacological effect as a consequence of their high alpha 1 beta 2 gamma 2 subtype selectivity observed in vitro.

Animals↗