Abstract
CP-MLR/PLS DIRECTED QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP STUDY ON THE SMALL-MOLECULE MODULATORS OF THE MEDIATOR COMPLEX-ASSOCIATED KINASES CDK8 AND CDK19: THE PYRIDINE DERIVATIVES

Dinesh Kumar Meena, Mukesh Meena, Brij Kishore Sharma,* and Raghuraj Parihar

ABSTRACT

The CDK8 and CDK19 inhibition activity of pyridine derivatives has been quantitatively analyzed in terms of Dragon descriptors. The statistically validated quantitative structure-activity relationship (QSAR) models provided rationales to explain the inhibition activities of these congeners. The descriptors identified through combinatorial protocol in multiple linear regression (CP-MLR) analysis for the CDK8 inhibitory activity have highlighted the role of 1st and 2nd order information content indices (IC1 and IC2, respectively), 2D Petitjean shape index (PJI2), Galvez topological charge index of 10th order (GGI10) and 1st order mean topological charge index (IGI1) to rationalize the activity. Atomic properties such as atomic van der Waals volumes and polarizabilities in terms of Mv, and Moran and Geary autocorrelations (MATS3v, GATS1v and GATS3p) in addition to the number of oxygen atoms (nO) have shown prevalence to model the CDK8 inhibitory activity. 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. The derived QSAR models for the CDK19 inhibitory activity have revealed that the structural information content of 2nd order neighborhood symmetry (SIC2), atomic polarizabilities weighted Geary autocorrelations of lag 5 and 7 (GATS5p and GATS7p) and atomic masses weighted lowest eigenvalue n.2 of Burden matrix (BELm2) played a pivotal role in rationalization of CDK19 inhibition activity of titled compounds. Additionally, presence of H attached to C0(sp3) with 1X attached to next carbon (H-052) and CH3R/CH4 (C-001) type structural fragment and lesser number or absence of tertiary aliphatic amines functionality (nNR2) are also predominant to explain CDK19 inhibition actions of pyridine derivatives.

Keywords: QSAR, CDK8 and CDK19 inhibitors, Combinatorial protocol in multiple linear regression (CP-MLR) analysis, PLS, Dragon descriptors, Pyridine derivatives.


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