Harnessing natural compounds for PIM-1 kinase inhibition: A synergistic approach using virtual screening, molecular
1Department of Health Informatics, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia . m.quazi@qu.edu.sa.
Abstract:
Cancer has substantial economic ramifications for healthcare systems. PIM kinases, specifically PIM-1, are commonly upregulated in different types of cancers, thereby promoting cancer development. PIM-1 inhibitors have garnered interest for their potential efficacy in cancer therapy. This study used computational methods to screen a library of 7,600 natural compounds targeting the PIM-1 active site. Five top candidates-ZINC00388658, ZINC00316459, ZINC00197401, ZINC00001673, and ZINC00316479-were selected for subsequent interaction studies, which involved molecular dynamics simulations (MDS) and free energy calculation using the MMPBSA method. These compounds interacted with key PIM-1 residues and had multiple common binding site interactions with the co-crystallized ligand 6YN, which was used as a control. Furthermore, the selected compounds exhibited favorable drug-like properties and stable docked complexes during a 200-ns molecular dynamics simulation, followed by MMPBSA analysis. Among the candidates, ZINC00388658 had the most favorable binding energy profile, indicating exceptional stability and intense interaction with PIM 1. This makes ZINC00388658 the most promising candidate for further development as a PIM-1 inhibitor. These findings suggest that ZINC00388658 and other promising compounds hold significant potential for developing new cancer therapies that target PIM-1.
Insights
Computational screening identified natural compounds as potential PIM-1 inhibitors for cancer therapy. ZINC00388658 showed the most promising stability and interaction with PIM-1, suggesting its potential for new cancer treatments.
Area of Science:
- Computational chemistry
- Molecular biology
- Drug discovery
Background:
- PIM kinases, particularly PIM-1, are frequently overexpressed in various cancers, driving tumor progression.
- Targeting PIM-1 with inhibitors is a promising strategy for novel cancer therapies.
Purpose of the Study:
- To computationally screen a large library of natural compounds for potential PIM-1 inhibitors.
- To evaluate the binding affinity, drug-like properties, and stability of top candidate compounds.
Main Methods:
- Virtual screening of 7,600 natural compounds against the PIM-1 active site.
- Molecular dynamics simulations (MDS) and Molecular Mechanics with the Poisson-Boltzmann Surface Area (MMPBSA) method for interaction analysis.
- Comparison with a co-crystallized ligand (6YN) for validation.
Main Results:
- Five compounds (ZINC00388658, ZINC00316459, ZINC00197401, ZINC00001673, ZINC00316479) were identified as top candidates.
- Selected compounds demonstrated favorable drug-like properties and stable interactions with key PIM-1 residues.
- ZINC00388658 exhibited the most favorable binding energy and stability, indicating potent PIM-1 inhibition.
Conclusions:
- ZINC00388658 is a highly promising candidate for developing new PIM-1 targeted cancer therapies.
- The identified natural compounds warrant further investigation for their therapeutic potential in oncology.
Related Concept Videos
01:42Phosphoinositides and PIPs
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...