Abstract

QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP (QSAR) STUDY ON THE CDK2 INHIBITORY ACTIVITY OF 4- BENZOYLAMINO-1H-PYRAZOLE-3-CARBOXAMIDE DERIVATIVES

Meena Dinesh Kumar and Sharma Brij Kishore*

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Abstract

The CDK 2 and 1 inhibition activity of 4-benzoylamino-1H-pyrazole- 3-carboxamide derivatives has been quantitatively analyzed in terms of Dragon descriptors. The statistically validated quantitative structureactivity relationship (QSAR) models provided rationales to explain the inhibition activities of these congeners. The descriptors identified through combinatorial protocol in multiple linear regression (CPMLR) analysis for the CDK2 inhibitory activity have highlighted the role of E-state topological parameter (TIE), path/walk 4-Randic shape index (PW4), atomic masses weighted Moran autocorrelation of lag 6 (MATS6m) and fragment based polar surface area (PSA). Atom centered fragments, R--CH--X (C-027) and RCO-NN-X=X (N-072) have also shown prevalence to model the CDK2 inhibitory activity. The statistics emerged from the test sets have validated the identified significant models. PLS analysis has also corroborated the dominance of CP-MLR identified descriptors. Applicability domain analysis revealed that the suggested model matches the high quality parameters with good fitting power and the capability of assessing external data and all of the compounds was within the applicability domain of the proposed model and were evaluated correctly. For the CDK1 inhibitory activity, a higher value of descriptors MATS7m (atomic masses weighted Moran autocorrelations of lag 7), SPI (superpendentic index), MSD (Balaban mean square distance index) and MLOGP (Moriguchi octanol-water partition coefficient, logP) will be helpful to augment the activity. On the other hand lower values of descriptors nO (number of oxygen atoms), MATS8v (atomic van der Waals volumes weighted Moran autocorrelations of lag 8), TIE (E-state topological parameter) and JGI4 (mean topological charge index of order 4) advocates that a lower value of these will be beneficial for the activity.

Keywords: QSAR, CDK2 inhibitors, Combinatorial protocol in multiple linear regression (CP-MLR) analysis, Dragon descriptors, 4-benzoylamino-1H-pyrazole-3-carboxamide derivatives.