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

Abstract

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 (r²) 0.8651, cross validation coefficient (q²) 0.7609. Furthermore, the predicted correlation coefficient (r² _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

Keywords:

• 3D-QSAR
• molecular docking
• cancer
• PIM-1 kinase
• molecular dynamics
• PLS

Acknowledgements

The corresponding author Ravindra Kulkarni expresses gratitude to the Principal, Poona College of Pharmacy, Pune for his constant encouragement and the Vlife Sciences to provide free trial software license for the research work and we would like to thank Ritesh, Harshali and Mehavi for their valuable help. First author Khandekar Mangala expresses gratitude to Mr. J. S. Shinge Assistant Professor who received one-month trial license from Schrodinger Bangalore and Schrodinger Bangalore for their indispensable help by granting one month trial license.

Author’s contribution

All the authors have equally contributed to the research work and approved the final version of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.