CP-MLR/PLS directed quantitative structure-activity relationship study on the CDK8 inhibitory activity: The derivatives of naphthyridine and isoquinoline

The CDK8 and 7dF3 inhibition activity of naphthyridine and isoquinoline derivatives have 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 CP-MLR analysis for the CDK8 inhibitory activity have highlighted the role of sum of the topological distances between N..N (T(N..N)), distance/detour ring index of order 6 (D/Dr06), aromatic ratio (ARR), number of double bonds (nDB), number of 6-membered rings (nR06), number of sulphur atoms (nS), number of unsubstituted sp2 hybridized aromatic carbon atoms (nCaH), number of aliphatic N hydrazines (nN-N), number of aromatic primary amines (nNH2Ph) and certain atom centered fragments such as R--CH--R (C-024), X--CR..X (C-034), H attached to C1(sp3)/C0(sp2) (H-047) and RCO-N</>N-X=X (N-072) to quantify the inhibitory actions. The highest eigen value n.2 of Burden matrix/weighted by atomic polarizabilites (BEHp2) and atomic Sanderson electronegativities weighted Geary autocorrelation of lag 8 (descriptor GATS8e) have also 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 models obtained from the descriptor pool that was chosen for the CDK8 inhibitory activity is able to explain nearly 74% variance in the observed 7dF3 activities of titled compounds.