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Discovery of novel CDK8 inhibitors using multiple crystal structures in docking-based virtual screening
Taijin Wang1, Zhuang Yang1, Yongguang Zhang1
1State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
Abstract:
The cyclin dependent kinase CDK8, along with Med12 and Med13, form the kinase module of the Mediator complex. CDK8 expression associates with the activation of β-catenin in colon and gastric cancers. Herein, we applied docking-based virtual screening (VS) using the multiple crystal structures to identify several potent CDK8 inhibitors. The appropriate use of multiple crystal structures obtained a better enrichment of CDK8 conformations to cope with the protein flexibility. Later on, the 2D similarity search was used to find the derivatives of the high inhibitory CDK8 inhibitors we discovered by VS. Finally, we measured the dose response behaviors, the IC50 values of compound W-34, W-37, W-8, WS-2 are 6.5 nM, 36 nM, 93 nM, 9 nM, respectively. These novel leads provided good starting points to design and synthesis a series of highly selective and potent CDK8 inhibitors.
Insights
Researchers identified potent CDK8 inhibitors using virtual screening. These compounds, including W-34 and WS-2 with nanomolar IC50 values, show promise for developing new cancer therapies targeting CDK8.
Area of Science:
- Medicinal Chemistry
- Structural Biology
- Cancer Biology
Background:
- Cyclin-dependent kinase 8 (CDK8) is part of the Mediator complex and linked to cancer progression.
- CDK8 activation correlates with β-catenin signaling in colon and gastric cancers.
Purpose of the Study:
- To identify novel, potent inhibitors of CDK8 using computational methods.
- To explore structure-based drug design strategies for CDK8.
Main Methods:
- Docking-based virtual screening (VS) against multiple CDK8 crystal structures.
- 2D similarity searches to identify potential inhibitor derivatives.
- In vitro dose-response assays to determine IC50 values.
Main Results:
- Virtual screening successfully identified potent CDK8 inhibitors.
- Compounds W-34, W-37, W-8, and WS-2 exhibited IC50 values in the nanomolar range (6.5 nM, 36 nM, 93 nM, 9 nM, respectively).
- Multiple crystal structures improved the VS enrichment by accounting for protein flexibility.
Conclusions:
- The identified compounds serve as promising starting points for developing selective and potent CDK8 inhibitors.
- This study highlights the utility of docking-based VS with diverse protein conformations for drug discovery.
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