Uncovering potential CDK9 inhibitors from natural compound databases through docking-based virtual screening and MD
Pooja Singh1, Vikas Kumar2,3, Tae Sung Jung4
1Division of Applied Life Science, (BK21 Four), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Gyeongsang National University (GNU), 501 Jinju-Daero, Jinju, 52828, Republic of Korea.
Context:
Cyclin-dependent kinase 9 (CDK9) plays a significant role in gene regulation and RNA polymerase II transcription under basal and stimulated conditions. The upregulation of transcriptional homeostasis by CDK9 leads to various malignant tumors and therefore acts as a valuable drug target in addressing cancer incidences. Ongoing drug development endeavors targeting CDK9 have yielded numerous clinical candidate molecules currently undergoing investigation as potential CDK9 modulators, though none have yet received Food and Drug Administration (FDA) approval.
Methods:
In this study, we employ in silico approaches including the molecular docking and molecular dynamics simulations for the virtual screening over the natural compounds library to identify novel promising selective CDK9 inhibitors. The compounds derived from the initial virtual screening were subsequently employed for molecular dynamics simulations and binding free energy calculations to study the compound's stability under virtual physiological conditions. The first-generation CDK inhibitor Flavopiridol was used as a reference to compare with our novel hit compound as a CDK9 antagonist. The 500-ns molecular dynamics simulation and binding free energy calculation showed that two natural compounds showed better binding affinity and interaction mode with CDK9 receptors over the reference Flavopiridol. They also showed reasonable figures in the predicted absorption, distribution, metabolism, excretion, and toxicity (ADMET) calculations as well as in computational cytotoxicity predictions. Therefore, we anticipate that the proposed scaffolds could contribute to developing potential and selective CDK9 inhibitors subjected to further validations.
Insights
Two natural compounds show promise as selective Cyclin-dependent kinase 9 (CDK9) inhibitors. These novel CDK9 antagonists exhibit superior binding affinity and interaction compared to Flavopiridol, with favorable ADMET predictions for cancer therapy development.
Area of Science:
- Biochemistry
- Molecular Biology
- Computational Chemistry
Background:
- Cyclin-dependent kinase 9 (CDK9) is crucial for gene regulation and transcription, and its dysregulation is linked to various cancers.
- CDK9 is a valuable drug target for cancer treatment, but no CDK9 inhibitors have received FDA approval yet.
Purpose of the Study:
- To identify novel, selective CDK9 inhibitors from a natural compounds library using in silico methods.
- To evaluate the binding affinity, stability, and drug-likeness of potential CDK9 inhibitors.
Main Methods:
- Virtual screening using molecular docking and molecular dynamics simulations.
- Binding free energy calculations and ADMET predictions.
- Comparison with the reference inhibitor Flavopiridol.
Main Results:
- Two natural compounds demonstrated superior binding affinity and interaction with CDK9 compared to Flavopiridol.
- The identified compounds exhibited favorable predicted ADMET profiles and computational cytotoxicity.
- The study successfully identified promising scaffolds for selective CDK9 inhibitor development.
Conclusions:
- The identified natural compounds represent potential lead candidates for developing novel and selective CDK9 inhibitors.
- These findings warrant further experimental validation for therapeutic applications in cancer treatment.
