Reconnoitering imidazopyridazines as anticancer agents based on virtual modelling approach: quantitative structure activity relationship, molecular docking and molecular dynamics

Cancer is an unimpeded growth of cells leading to metathesis of cancer and eventually spread throughout the body. PIM kinases are the members of the serine threonine kinase playing role in cancer progression, differentiation and proliferation. Till date there is no single drug targeting PIM-1 kinase in the market, that has made itself a target in limelight for the discover of new anticancer agents. The contemporary research focusses on the development of new inhibitors of PIM-1 kinase by application of ligand-based and structure-based perspective of drug discovery namely 3D-QSAR, molecular docking and dynamics. The following study stated the correlation amid structural and biological activity of the compounds employing 3D-QSAR analysis. Three 3D-QSAR models were generated using 33 molecules from which the excellent model stated an encouraging conventional correlation coefficient (r(2)) 0.8651, cross validation coefficient (q(2)) 0.7609. Furthermore, the predicted correlation coefficient (r(2) (pred)) 0.6274, respectively. Molecular docking studies revealed that the most active compound 26 resided in the active pocket of PIM-1 kinase establishing hydrogen bond interactions with Asp186 in the DFG motif; similarly, all other molecules were engaged within the active site of the PIM-1 kinase. Moreover, molecular dynamics simulation study stated the stability of the ligand in the active site of PIM-1 kinase protein by developing two hydrogen bonds throughout the trajectory of 100 ns. In nutshell, the output stated the successful application of ligand and structure-based strategy for the development of novel PIM-1 kinase inhibitors as anticancer agents.Communicated by Ramaswamy H. Sarma

Automated summary

This study used ligand-based and structure-based methods to develop new inhibitors of PIM-1 kinase as anticancer agents. 3D-QSAR analysis revealed the correlation between compound structures and biological activities. Molecular docking and dynamics simulations showed that compound 26 had the highest activity and interacted with the active site of PIM-1 kinase through hydrogen bonds. The results demonstrated the successful application of ligand and structure-based strategies in drug development.