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Published on: January 22, 2019
Identification of Activated Cdc42-Associated Kinase Inhibitors as Potential Anticancer Agents Using
Vikas Kumar1,2, Raj Kumar3, Shraddha Parate4,5
1Department of Bio & Medical Big Data (BK4 Program), Division of Life Science, Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Republic of Korea.
Background:
Activated Cdc42-associated kinase (ACK1) is essential for numerous cellular functions, such as growth, proliferation, and migration. ACK1 signaling occurs through multiple receptor tyrosine kinases; therefore, its inhibition can provide effective antiproliferative effects against multiple human cancers. A number of ACK1-specific inhibitors were designed and discovered in the previous decade, but none have reached the clinic. Potent and selective ACK1 inhibitors are urgently needed.
Methods:
In the present investigation, the pharmacophore model (PM) was rationally built utilizing two distinct inhibitors coupled with ACK1 crystal structures. The generated PM was utilized to screen the drug-like database generated from the four chemical databases. The binding mode of pharmacophore-mapped compounds was predicted using a molecular docking (MD) study. The selected hit-protein complexes from MD were studied under all-atom molecular dynamics simulations (MDS) for 500 ns. The obtained trajectories were ranked using binding free energy calculations (ΔG kJ/mol) and Gibb's free energy landscape.
Results:
Our results indicate that the three hit compounds displayed higher binding affinity toward ACK1 when compared with the known multi-kinase inhibitor dasatinib. The inter-molecular interactions of Hit1 and Hit3 reveal that compounds form desirable hydrogen bond interactions with gatekeeper T205, hinge region A208, and DFG motif D270. As a result, we anticipate that the proposed scaffolds might help in the design of promising selective ACK1 inhibitors.
Insights
Researchers developed a pharmacophore model to identify novel inhibitors of Activated Cdc42-associated kinase (ACK1), a key target in cancer. Three hit compounds showed promising binding affinity, suggesting potential for new cancer therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Activated Cdc42-associated kinase (ACK1) is crucial for cell growth, proliferation, and migration.
- ACK1's role in receptor tyrosine kinase signaling makes it a target for antiproliferative cancer therapies.
- Despite previous efforts, no ACK1-specific inhibitors have reached clinical application, highlighting the need for potent and selective agents.
Purpose of the Study:
- To rationally design and identify novel, potent, and selective ACK1 inhibitors.
- To utilize computational methods for screening and validating potential drug candidates against ACK1.
Main Methods:
- A pharmacophore model was constructed using ACK1 crystal structures and known inhibitors.
- A drug-like database was screened using the pharmacophore model.
- Molecular docking and 500 ns all-atom molecular dynamics simulations were performed.
- Binding free energy calculations and Gibb's free energy landscape analysis were used for ranking.
Main Results:
- Three hit compounds demonstrated superior binding affinity to ACK1 compared to dasatinib.
- Hit compounds formed favorable interactions, including hydrogen bonds with key residues like T205, A208, and D270.
- The identified interactions support the potential of these compounds as ACK1 inhibitors.
Conclusions:
- The study successfully identified potential ACK1 inhibitor scaffolds through computational screening.
- The findings provide a foundation for the development of novel selective ACK1 inhibitors for cancer treatment.
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