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Exploring the interaction between human focal adhesion kinase and inhibitors: a molecular dynamic simulation and free
Jiu-Yu Zhan1, Ji-Long Zhang1, Yan Wang1
1a State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry , Jilin University , Changchun 130023 , P.R. China.
Abstract:
Focal adhesion kinase is an important target for the treatment of many kinds of cancers. Inhibitors of FAK are proposed to be the anticancer agents for multiple tumors. The interaction characteristic between FAK and its inhibitors is crucial to develop new inhibitors. In the present article, we used Molecular Dynamic (MD) simulation method to explore the characteristic of interaction between FAK and three inhibitors (PHM16, TAE226, and ligand3). The MD simulation results together with MM-GB/SA calculations show that the combinations are enthalpy-driven process. Cys502 and Asp564 are both essential residues due to the hydrogen bond interactions with inhibitors, which was in good agreement with experimental data. Glu500 can form a non-classical hydrogen bond with each inhibitor. Arg426 can form electrostatic interactions with PHM16 and ligand3, while weaker with TAE226. The electronic static potential was employed, and we found that the ortho-position methoxy of TAE226 has a weaker negative charge than the meta-position one in PHM16 or ligand3. Ile428, Val436, Ala452, Val484, Leu501, Glu505, Glu506, Leu553, Gly563 Leu567, Ser568 are all crucial residues in hydrophobic interactions. The key residues in this work will be available for further inhibitor design of FAK and also give assistance to further research of cancer.
Insights
Focal adhesion kinase (FAK) inhibitors show promise as anticancer agents. Molecular dynamics simulations reveal key interactions between FAK and inhibitors, guiding future drug design for cancer treatment.
Area of Science:
- Biochemistry
- Computational Chemistry
- Oncology
Background:
- Focal adhesion kinase (FAK) is a significant therapeutic target for various cancers.
- Developing novel FAK inhibitors is crucial for effective anticancer therapies.
- Understanding FAK-inhibitor interactions is key to designing potent drugs.
Purpose of the Study:
- To investigate the interaction characteristics between FAK and three inhibitors (PHM16, TAE226, ligand3).
- To utilize Molecular Dynamics (MD) simulations and MM-GB/SA calculations for this exploration.
- To identify key residues involved in FAK-inhibitor binding for future drug design.
Main Methods:
- Employed Molecular Dynamics (MD) simulation techniques.
- Utilized MM-GB/SA calculations to analyze binding thermodynamics.
- Analyzed electronic static potential to understand charge distribution.
Main Results:
- FAK-inhibitor interactions are primarily enthalpy-driven.
- Cys502 and Asp564 are critical for hydrogen bonding with inhibitors.
- Hydrophobic interactions involve residues Ile428, Val436, Ala452, Val484, Leu501, Glu505, Glu506, Leu553, Gly563, Leu567, and Ser568.
Conclusions:
- Identified essential residues (Cys502, Asp564, Glu500, Arg426) and hydrophobic residues crucial for FAK inhibitor binding.
- Findings align with experimental data, validating the simulation approach.
- The identified key residues will aid in the rational design of new FAK inhibitors for cancer therapy.
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