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Updated: Jul 31, 2025
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Reconnoitering imidazopyridazines as anticancer agents based on virtual modelling approach: quantitative structure
Khandekar Mangala1,2, Walhekar Vinayak3, Choudhary Aasiya1,2
1Department of Pharmaceutical Chemistry, SVERIs College of Pharmacy, Gopalpur, India.
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.
Insights
Researchers developed novel PIM-1 kinase inhibitors for cancer treatment using computational methods. These PIM-1 kinase inhibitors show promise as new anticancer agents by targeting cell proliferation and progression.
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.
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