Discovery of novel tetrahydropyrido-pyrazole based cathepsin s inhibitors: implications of two dimensional quantitative structure activity relationship analysis
By: Kushwaha, Sneha
.
Contributor(s): Paliwal, S. K.
Publisher: Mumbai Indian Journal of Pharmaceutical Science 2022Edition: Vol.84(5), Sep-Oct.Description: 1161-1170p.Subject(s): PHARMACEUTICSOnline resources: Click here
In:
Indian journal of pharmaceutical sciencesSummary: 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.
| Item type | Current location | Call number | Status | Date due | Barcode | Item holds |
|---|---|---|---|---|---|---|
Articles Abstract Database
|
School of Pharmacy Archieval Section | Not for loan | 2023-1126 |
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.
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