Structural Insight for Imidazopyridazines as Malarial Kinase PfPK7 Inhibitors Using QSAR Techniques

Nitendra      K. Sahu; D.      V. Kohli

Abstract

With a view to the rational design of a selected series of 35 imidazopyridazine derivatives, 2D and 3D QSAR models have been developed for the prediction of antimalarial activity. The statistically best 2D QSAR model having r2 = 0.9242 and q2 = 0.8691 with pred_r2 = 0.9206 was developed by SW-MLR and best 3D QSAR model having q2 = 0.8607 with pred_r2 = 0.8332 was developed by k-nearest neighbor molecular field analysis (kNN-MFA). Molecular docking study was also carried out to better understand of the interactions between PfPK7 enzyme target (pdb: 2pnm) and inhibitors in this series. The docking study suggests that these PfPK7 inhibitors interact with Met120, Lys55, Tyr117, Asp123, Leu179, Leu34, Asn35, Ala53, Glu88, Leu101, Tyr119, Ser124, Ser189 and Asp190 amino acid residues of protein PfPK7. Both QSAR and docking studies of such derivatives provide guidance for further lead optimization and designing of more potent PfPK7 inhibitors.

Keywords: PfPK7, kNN-MFA, Antimalarial Agents, QSAR, docking, Imidazopyridazines, MLR, Chloroquine, plasmodial kinase, imidazopyridazine