The pharmacological profiles of benzodiazepines (Bzs) are due to their GABAA receptor modulating property, consequently benzodiazepine binding site (BBS) is an interesting target for developing novel drugs with potential effects on anxiety. Several types of compounds, such as the pyrazolo-quinolinones, are known to bind the BBS with high affinity, showing a continuous pharmacological activity as agonists, inverse agonists or antagonists.
A series of novel 2-aryl-2H-pyrazolo[4,3-c]quinolin-3-ones derivatives were synthetized. Multistep synthesis was carried out from aromatic amines and diethyl ethoxymethylenemalonate via Gould-Jacobs reaction, and the further treatment with different hydrazines gave the pyrazolo-quinolinone nucleus (Figure 1). In this work we present the results obtained concerning the molecular docking for this series of novel compounds. The homology model of the GABAA receptor used in this study was constructed as described by Mercado et al. The structure was then checked for polar hydrogens, and partial atomic charges were those obtained from the parm99 force field in Amber8. All novel ligands were built, and minimized, and their electrostatic charges computed by the HF6-311G** level in the Gaussian98 program. For molecular docking a 3D grid was created by the AutoGrid3.0 algorithm in the BBS binding site to evaluate the binding energies between each ligand and the GABAA receptor. The Lakmarkian Genetic algorithm of AutoDock3.0 software was used for the molecular docking. The orientation with the best binding has the lower total energy and the cluster of highest number of bindings represents a higher probability of binding. All the modelated compounds bind with high docking energy in the BBS as the reference compounds, but their tridimensional disposition inside the binding pocket differs according to each substituent present in the pyrazoloquinolinone nucleus.
