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Molecular Dynamics Simulations Based on 1-Phenyl-4-Benzoyl-1-Hydro-Triazole ERRα Inverse Agonists
Zhipei Gao1, Yongli Du1, Xiehuang Sheng2
1School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), 3501 Da Xue Road, Jinan 250353, China.
Abstract:
Estrogen-related receptor α (ERRα), which is overexpressed in a variety of cancers has been considered as an effective target for anticancer therapy. ERRα inverse agonists have been proven to effectively inhibit the migration and invasion of cancer cells. As few crystalline complexes have been reported, molecular dynamics (MD) simulations were carried out in this study to deepen the understanding of the interaction mechanism between inverse agonists and ERRα. The binding free energy was analyzed by the MM-GBSA method. The results show that the total binding free energy was positively correlated with the biological activity of an inverse agonist. The interaction of the inverse agonist with the hydrophobic interlayer composed of Phe328 and Phe495 had an important impact on the biological activity of inverse agonists, which was confirmed by the decomposition of energy on residues. As Glu331 flipped and formed a hydrogen bond with Arg372 in the MD simulation process, the formation of hydrogen bond interaction with Glu331 was not a necessary condition for the compound to act as an inverse agonist. These rules provide guidance for the design of new inverse agonists.
Insights
Estrogen-related receptor α (ERRα) inverse agonists show promise in cancer therapy by inhibiting cell migration. Molecular dynamics simulations reveal key interactions influencing their effectiveness, guiding new drug design.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Estrogen-related receptor α (ERRα) is overexpressed in various cancers and is a target for anticancer therapy.
- ERRα inverse agonists inhibit cancer cell migration and invasion, but their interaction mechanisms are not fully understood due to limited crystalline complex data.
Purpose of the Study:
- To elucidate the interaction mechanism between ERRα inverse agonists and ERRα using molecular dynamics (MD) simulations.
- To correlate binding free energy with the biological activity of inverse agonists.
Main Methods:
- Molecular dynamics (MD) simulations were employed to study the interactions.
- The MM-GBSA method was used to analyze binding free energy.
- Energy decomposition analysis was performed on residues to identify key interactions.
Main Results:
- Total binding free energy positively correlated with the biological activity of inverse agonists.
- Interaction with the hydrophobic interlayer (Phe328, Phe495) significantly impacts biological activity.
- Hydrogen bonding with Glu331 is not essential for inverse agonist activity, as demonstrated by its interaction with Arg372.
Conclusions:
- The study provides insights into the molecular mechanisms underlying ERRα inverse agonist activity.
- Key interactions, particularly with hydrophobic residues, are crucial for efficacy.
- Findings offer guidance for the rational design of novel and more effective ERRα inverse agonists for cancer treatment.
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