Reconnoitering imidazopyridazines as anticancer agents based on virtual modelling approach: quantitative structure...

Area of Science:

• Medicinal Chemistry
• Computational Drug Discovery
• Oncology

Background:

• PIM kinases are serine/threonine kinases crucial for cancer progression, differentiation, and proliferation.
• There are currently no drugs targeting PIM-1 kinase on the market, making it a significant target for new anticancer agent discovery.

Purpose of the Study:

• To develop novel PIM-1 kinase inhibitors as potential anticancer agents.
• To explore the correlation between structural and biological activity of compounds using computational approaches.

Main Methods:

• Utilized ligand-based and structure-based drug discovery perspectives, including 3D-Quantitative Structure-Activity Relationship (3D-QSAR) analysis.
• Performed molecular docking to assess compound binding within the PIM-1 kinase active site.
• Conducted molecular dynamics simulations to evaluate ligand stability in the kinase active site.

Main Results:

• Three 3D-QSAR models were generated, with the best model showing a high conventional correlation coefficient (r=0.8651) and cross-validation coefficient (q²=0.7609).
• Molecular docking identified compound 26 as highly active, forming hydrogen bonds with Asp186 in the PIM-1 kinase active site.
• Molecular dynamics simulations confirmed the stability of the docked ligands within the PIM-1 kinase active site over a 100 ns trajectory.

Conclusions:

• The study successfully applied ligand-based and structure-based strategies to design novel PIM-1 kinase inhibitors.
• The developed compounds demonstrate potential as effective anticancer agents by targeting PIM-1 kinase.