COMPUTER AIDED DESIGN OF SELECTIVE CALCIUM CHANNEL BLOCKERS: USING PHARMACOPHORE – BASED AND DOCKING SIMULATIONS

In the present study, 3-D QSAR analysis was performed on the previously synthesized and evaluated derivatives of novel 2-arylthiazolidinones as selective analgesic N-type calcium channel blockers. Calcium Channel blockers is the molecular target responsible for the treatment of neuropathic and inflammatory pain. The 3D-QSAR study based on the principle of the alignment of pharmacophoric features by PHASE module of Schrodinger suite has been carried out on the same set of calcium channel blockers. Statistically significant 3-D QSAR model (R²=0.9288) were generated using 21 molecules in the training set. The predictive ability of model was determined using a randomly chosen test set of 6 molecules which gave predictive correlation coefficients (R²_pred) of 0.946 for 3-D models, indicating good predictive power. PHASE pharmacophore hypothesis AAHR.13 may correspond very closely to the interactions recorded in the active site of the ligand bound complex.  These studies produced models with high correlation coefficient and good predictive abilities. Docking studies were also carried out wherein these analogues were docked into the active sites of COX-2 to analyze the receptor-ligand interactions that confer selectivity for COX-2. Compound 2 have the highest dock score (-7.28).  In the active site, there are some strong hydrogen-bonding interactions observed between residues GLU67, ALA103, ASP96, SER184 and ASP22. Additionally a correlation of the quantitative structure –activity relationship data and the docking results is found to validate each other and suggest the importance of the binding step in overall drug action.