Identification of novel CDK 9 inhibitors based on virtual screening, molecular dynamics simulation, and biological
Mingfei Wu1, Jianfei Han1, Zhicheng Liu1
1The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The key laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei 230032, China.
Aims:
Cyclin-dependent kinase 9 (CDK9) is a member of the CDK subfamily and plays a major role in the regulation of transcriptional elongation. It has attracted widespread attention as a therapeutic target for cancer. Here, we aimed to explore novel CDK 9 inhibitors by using a hybrid virtual screening strategy.
Main Methods:
A hybrid virtual screening strategy was constructed with computer-aided drug design (CADD). First, compounds were filtered in accordance with Lipinski's rule of five and adsorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Second, a 3D-QSAR pharmacophore model was built and used as a 3D query to screen the obtained hit compounds. Third, the hit compounds were subjected to molecular docking studies. Fourth, molecular dynamics (MD) simulations were performed on CDK9 in complex with the final hits to examine the structural stability. Finally, CDK9 kinase biochemical assay was performed to identify the biological activity of the hit compounds.
Key Findings:
Seven hit compounds were screened out. These hit compounds showed drug-like properties in accordance with Lipinski's rule of five and ADMET. Complexes involving the six hit compounds bound to CDK9 exhibited good structural stability in the MD simulation. Furthermore, these six hit compounds had strong inhibitory activity against CDK9 kinase. In particular, hit 3 showed the most promising activity with the percentage of 71%.
Significance:
The six hit compounds may be promising novel CDK9 inhibitors, and the hybrid virtual screening strategy designed in this study provides an important reference for the design and synthesis of novel CDK9 inhibitors.
Insights
Researchers identified six novel compounds with strong inhibitory activity against cyclin-dependent kinase 9 (CDK9), a key target in cancer therapy. This discovery utilized a hybrid virtual screening strategy, offering a new approach for developing CDK9 inhibitors.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Chemistry
Background:
- Cyclin-dependent kinase 9 (CDK9) is crucial for transcriptional elongation and a significant therapeutic target in oncology.
- Developing novel CDK9 inhibitors is essential for advancing cancer treatment strategies.
Purpose of the Study:
- To identify novel inhibitors of Cyclin-dependent kinase 9 (CDK9) using a hybrid virtual screening approach.
- To evaluate the drug-like properties, binding stability, and inhibitory activity of potential CDK9 inhibitors.
Main Methods:
- A hybrid virtual screening strategy combining Lipinski's rule of five, ADMET filtering, 3D-QSAR pharmacophore modeling, and molecular docking.
- Molecular dynamics simulations were employed to assess the stability of CDK9-inhibitor complexes.
- Biochemical assays were conducted to determine the inhibitory activity of the screened compounds against CDK9 kinase.
Main Results:
- Seven hit compounds were identified with favorable drug-like and ADMET properties.
- Six of the hit compounds demonstrated stable binding to CDK9, confirmed by molecular dynamics simulations.
- These six compounds exhibited significant inhibitory activity against CDK9 kinase, with one compound showing 71% inhibition.
Conclusions:
- The identified six compounds represent promising novel inhibitors of CDK9.
- The employed hybrid virtual screening strategy serves as a valuable reference for future CDK9 inhibitor design and synthesis efforts.
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