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Structure-based virtual screening, molecular dynamics and MM-PBSA/GBSA analysis for the identification of novel CDK6
Manzoor Ahmad1, Muhammad Ajmal Khan2, Ashraf Ullah Khan3
1Department of Pharmacy, Faculty of Pharmaceutical Sciences, Abasyn University, Peshawar, 25000 Pakistan.
Abstract:
The present study was aimed to identify the novel compounds and explore the mechanism of the compounds from the library against prostate cancer by targeting the CDK6 signaling. The CDK6 signaling is involved in the cell cycle regulation and gain of function mutation paves the way for tumorigenesis in various cancers including the prostate. The virtual screening was performed against the CDK6 protein using Enamine compound library (Phenotypic screening library) containing 5760 compounds to obtain the top hits based on the binding energy and pharmacokinetic profile. Based on the virtual screening results, the top 5 compounds were selected for further studies including the MD simulation and binding free energy calculations using MM-PBSA and MM-GBSA. The MD simulation analysis was conducted to assess the dynamic stability of the complexes following virtual screening. The results showed that compounds 2231 (Z465849926), 2267 (Z56774766), 2760 (Z19047271), 3765 (Z1203029456), and 4612 (Z26475533) exhibited stable RMSD and no marked fluctuations were observed for 50 ns simulation. Similarly, the RMSF analysis and RoG were in the acceptable range following binding of the ligands with the protein. Similarly, the compounds formed a variable number of hydrogen bonds with the target protein during the simulation. The binding free energies calculation suing MM-PBSA and MM-GBSA revealed that compounds negative and favorable binding energies and validated the results of the MD simulation. The DFT calculations for the selected compounds to assess the stability and reactivity of the compounds using HOMO and LUMO energy gaps. Furthermore, pharmacokinetic studies were also conducted for the selected compounds. In conclusion, the selected compounds exhibited marked activity against the prostate cancer target and can be employed to deal with the prostate following comprehensive in vivo studies.
Supplementary Information:
The online version contains supplementary material available at 10.1007/s40203-026-00639-y.
Insights
Researchers identified novel compounds targeting CDK6 signaling for prostate cancer treatment. Virtual screening and molecular dynamics simulations confirmed stable binding and favorable interactions, suggesting potential therapeutic applications.
Area of Science:
- Computational chemistry and molecular modeling
- Oncology and cancer research
- Drug discovery and medicinal chemistry
Background:
- Cyclin-dependent kinase 6 (CDK6) signaling is crucial for cell cycle regulation.
- Aberrant CDK6 activity contributes to tumorigenesis in various cancers, including prostate cancer.
- Targeting CDK6 offers a potential therapeutic strategy for prostate cancer.
Purpose of the Study:
- To identify novel small molecules targeting CDK6 for prostate cancer therapy.
- To elucidate the binding mechanism and stability of identified compounds.
- To evaluate the pharmacokinetic properties of potential drug candidates.
Main Methods:
- Virtual screening of 5760 compounds from the Enamine library against the CDK6 protein.
- Molecular dynamics (MD) simulations, MM-PBSA, and MM-GBSA for binding free energy calculations.
- Density Functional Theory (DFT) for stability and reactivity analysis; pharmacokinetic profiling.
Main Results:
- Five compounds (2231, 2267, 2760, 3765, 4612) showed stable interactions with CDK6 during 50 ns MD simulations.
- Favorable binding free energies were calculated using MM-PBSA and MM-GBSA, validating MD results.
- DFT analysis indicated favorable stability and reactivity; pharmacokinetic studies were promising.
Conclusions:
- The identified compounds demonstrate significant potential as therapeutic agents against prostate cancer by targeting CDK6.
- These compounds exhibit stable binding and favorable pharmacokinetic profiles.
- Further in vivo studies are warranted to validate their efficacy and safety for clinical application.
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