Discovery of Novel Tetrahydropyrido-Pyrazole based Cathepsin S Inhibitors: Implications of Two Dimensional Quantitative Structure Activity Relationship Analysis
Department of Pharmacy, Banasthali University, Banasthali, Rajasthan 304022, India
Sneha Kushwaha, Department of Pharmacy, Banasthali University, Banasthali, Rajasthan 304022, India, E-mail: email@example.com
The anti-arthritic activity of cathepsin S enzyme has been acknowledged and regarded as an emerging target for the development of novel therapeutic agents for the treatment of various autoimmune disorders and other inflammatory diseases. Two dimensional-quantitative structure-activity relationships have been performed on a series of tetrahydropyrido-pyrazole nucleus using TSAR 3.3. Attempts have been made to derive and comprehend a correlation between biological activity (dependent variable) and descriptors (independent variables). The study was performed using 268 compounds (data set) by division into training and test set by the random selection method. 179 compounds generated a final quantitative structure-activity relationship model with the leave-out one row method of cross-validation to evaluate the predictive ability of the model. The most significant model with n=179, regression coefficient (0.851), correlation coefficient (0.725), cross-validated correlation coefficient (0.709), standard error (0.349), Fischer statistic value (114.706) was developed using multiple linear regression analysis. For partial least squares, a statistical significance value of 0.988 and a fraction of variance explained 0.723 were observed. A comparable partial least squares model with correlation coefficient (0.723) and neural model with correlation coefficient (0.731) indicated good internal predictability of the model. External test set validation provided correlation coefficient values of 0.708 and 0.706 for multiple linear regressions and partial least squares analysis respectively. Quantitative structure-activity relationship model indicated the importance of hydrophobic (log P (substituent 1)), topological (kier chi 5 (path) index (whole molecule)), electronic (bond dipole moment (substituent 5)) and (dipole moment Z component (substituent 1)) descriptors for the activity of Cathepsin S inhibitors. This study will be effective in designing novel and more potent cathepsin S inhibitors.