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Published on: August 7, 2021
Seeking mTORC1 Inhibitors Through Molecular Dynamics Simulation of Arginine Analogs Inhibiting CASTOR1
Liang Sun1,2, Xinyu Li3, Jun Pan1
1Department of Biology, Southern University of Science and Technology, Shenzhen, P.R. China.
Background:
Hyperactivity of the mechanistic target of rapamycin complex 1 (mTORC1) is implicated in a variety of diseases such as cancer and diabetes. Treatment may benefit from effective mTORC1 inhibition, which can be achieved by preventing arginine from disrupting the cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1)-GTPase-activating proteins toward RAGS subcomplex 2 (GATOR2) complex through binding with CASTOR1. An attractive idea is to determine analogues of arginine that are as competent as arginine in binding with CASTOR1, but without disrupting the CASTOR1-GATOR2 interaction.
Materials And Methods:
Molecular dynamics simulations were performed for binding of arginine analogues with CASTOR1 and binding free energy, hydrogen bond formation, and root mean squared deviation and root mean square fluctuation kinetics were then calculated.
Results:
The binding free energy calculations revealed that Nα-acetyl-arginine, citrulline, and norarginine have sufficient binding affinity with CASTOR1 to compete with arginine. The hydrogen bond analysis revealed that norarginine, Nα-acetyl-arginine and D-arginine have proficient H-bonds that can facilitate their entering the narrow binding pocket.
Conclusion:
Norarginine and Nα-acetyl-arginine are the top drug candidates for mTORC1 inhibition, with Nα-acetyl-arginine being the best choice.
Insights
Researchers identified Nα-acetyl-arginine and norarginine as promising drug candidates for inhibiting mTORC1, a target implicated in diseases like cancer and diabetes. Nα-acetyl-arginine emerged as the top choice for potential therapeutic applications.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Hyperactive mechanistic target of rapamycin complex 1 (mTORC1) signaling is linked to diseases including cancer and diabetes.
- mTORC1 inhibition may be therapeutically beneficial, potentially by preventing arginine from disrupting the CASTOR1-GATOR2 complex.
- Developing arginine analogues that bind CASTOR1 without disrupting the CASTOR1-GATOR2 interaction is a promising strategy.
Purpose of the Study:
- To identify arginine analogues that can bind to the cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1).
- To evaluate these analogues for their potential to inhibit mTORC1 hyperactivity.
- To find effective drug candidates for treating mTORC1-implicated diseases.
Main Methods:
- Utilized molecular dynamics simulations to study the binding of arginine analogues with CASTOR1.
- Calculated binding free energy to assess the affinity of analogues.
- Analyzed hydrogen bond formation, root mean squared deviation, and root mean square fluctuation kinetics.
Main Results:
- Nα-acetyl-arginine, citrulline, and norarginine demonstrated significant binding affinity with CASTOR1, capable of competing with arginine.
- Norarginine, Nα-acetyl-arginine, and D-arginine exhibited proficient hydrogen bonding patterns, facilitating entry into the CASTOR1 binding pocket.
- Binding free energy calculations supported the potential of these analogues as mTORC1 inhibitors.
Conclusions:
- Norarginine and Nα-acetyl-arginine are identified as leading drug candidates for mTORC1 inhibition.
- Nα-acetyl-arginine is highlighted as the most promising candidate due to its binding characteristics and potential efficacy.
- These findings offer a novel therapeutic avenue for diseases associated with mTORC1 hyperactivity.
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