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Identification and evaluation of pyrimidine based CDK6 inhibitors against glioblastoma using integrated computational
Hina Manzoor1, Muhammad Umer Khan2, Raima Rehman3
1Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan.
Abstract:
Cyclin-dependent kinases (CDKs) are crucial for controlling the cell cycle, and many malignancies are linked to CDK dysfunction. Therefore, CDKs are desirable targets for cancer treatment. Since abnormal expression of CDK4/6 is the etiology of glioblastoma, it is imperative to investigate the mechanism underlying CDK4/6 selectivity for inhibitors compared to CDK1/2, another member of the family. This study used a range of molecular docking and bioinformatics techniques to characterize the specific efficacy of ligands as inhibitors and their interaction with CDK6. Ligand-based virtual screening was performed using 6OQL'ligand. Using Maestro 12.5, ligands were docked to the interaction site of CDK6 with a reference co-crystallized ligand (CCL). The ligands were analyzed for absorption, distribution, metabolism, excretion, and toxicity (ADMET). Using density functional theory (DFT) analysis, the selected ligands were found to have substantial stability. One ligand, Mol_370, which closely resembles the characteristics of CCL, was simulated using molecular dynamics. The results revealed that amino acids and ligands interact at the CDK6 inhibitor-binding site via typical chemical interactions, such as hydrophobic interactions and hydrogen bonds, as demonstrated by the docking data. MD simulations revealed that Mol_ 370 is compatible with CCL, leading to changes in both structure and function. In conclusion, this study offers significant insights into the development and refinement of inhibitors that can successfully target CDK6 and produce novel cancer treatments.
Insights
This study identified Mol_370 as a promising inhibitor targeting Cyclin-dependent kinase 6 (CDK6), crucial for glioblastoma. Molecular docking and simulations reveal its potential for developing novel cancer therapies by interacting effectively with CDK6.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Cyclin-dependent kinases (CDKs) regulate the cell cycle; their dysfunction is implicated in various cancers.
- Abnormal expression of CDK4/6 drives glioblastoma development, necessitating targeted therapies.
- Understanding CDK6 inhibitor selectivity over CDK1/2 is critical for effective cancer treatment.
Purpose of the Study:
- To investigate the molecular mechanisms of CDK6 inhibitor selectivity.
- To identify and characterize novel ligands targeting CDK6.
- To provide insights for developing advanced CDK6-targeted cancer therapeutics.
Main Methods:
- Ligand-based virtual screening using a reference ligand (6OQL).
- Molecular docking of screened ligands to the CDK6 active site.
- Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analysis.
- Density Functional Theory (DFT) for ligand stability assessment.
- Molecular dynamics (MD) simulations of a lead compound (Mol_370).
Main Results:
- Docking analysis identified specific interactions (hydrophobic, hydrogen bonds) between ligands and CDK6.
- Mol_370 demonstrated high similarity to the reference co-crystallized ligand (CCL).
- MD simulations confirmed Mol_370's compatibility with CDK6, inducing structural and functional changes.
- DFT analysis indicated substantial stability for the selected ligands.
Conclusions:
- The study elucidates the interaction patterns of CDK6 inhibitors at the molecular level.
- Mol_370 shows significant potential as a lead compound for CDK6-targeted cancer therapy.
- Findings contribute to the rational design of selective CDK6 inhibitors for glioblastoma and other malignancies.
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