Identification of abemaciclib derivatives targeting cyclin-dependent kinase 4 and 6 using molecular dynamics, binding
Yanting Zhou1, Xiandeng Li2, Peifang Luo3
1Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnocentric of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China.
Abstract:
CDK4/6 plays a crucial role in various cancers and is an effective anticancer drug target. However, the gap between clinical requirements and approved CDK4/6 drugs is unresolved. Thus, there is an urgent need to develop selective and oral CDK4/6 inhibitors, particularly for monotherapy. Here, we studied the interaction between abemaciclib and human CDK6 using molecular dynamics simulations, binding free energy calculations, and energy decomposition. V101 and H100 formed stable hydrogen bonds with the amine-pyrimidine group, and K43 interacted with the imidazole ring via an unstable hydrogen bond. Meanwhile, I19, V27, A41, and L152 interacted with abemaciclib through π-alkyl interactions. Based on the binding model, abemaciclib was divided into four regions. With one region modification, 43 compounds were designed and evaluated using molecular docking. From each region, three favorable groups were selected and combined with each other to obtain 81 compounds. Among them, C2231-A, which was obtained by removing the methylene group from C2231, showed better inhibition than C2231. Kinase profiling revealed that C2231-A showed inhibitory activity similar to that of abemaciclib; additionally, C2231-A inhibited the growth of MDA-MB-231 cells to a greater extent than did abemaciclib. Based on molecular dynamics simulation, C2231-A was identified as a promising candidate compound with considerable inhibitory effects on human breast cancer cell lines.
Insights
Developing novel CDK4/6 inhibitors is crucial for cancer therapy. Researchers designed and evaluated new compounds, identifying C2231-A as a promising candidate with potent breast cancer cell inhibition.
Area of Science:
- Oncology
- Medicinal Chemistry
- Computational Biology
Background:
- Cyclin-dependent kinase 4 and 6 (CDK4/6) are vital targets in cancer therapy.
- Existing CDK4/6 inhibitors face limitations, necessitating the development of selective, oral agents for monotherapy.
Purpose of the Study:
- To investigate the interaction between abemaciclib and human CDK6.
- To design and identify novel CDK4/6 inhibitors with improved efficacy.
Main Methods:
- Molecular dynamics simulations and binding free energy calculations.
- Structure-based drug design and molecular docking.
- Kinase profiling and cell-based assays.
Main Results:
- Detailed abemaciclib-CDK6 interactions were elucidated, including hydrogen bonds and π-alkyl interactions.
- A novel compound, C2231-A, demonstrated superior inhibition compared to its parent compound C2231.
- C2231-A exhibited abemaciclib-like kinase activity and enhanced inhibition of MDA-MB-231 breast cancer cell growth.
Conclusions:
- Abemaciclib-CDK6 interaction analysis guided the design of new inhibitors.
- C2231-A is a promising drug candidate for breast cancer treatment, warranting further investigation.
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