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Identification of a Cryptic Pocket in Methionine Aminopeptidase-II Using Adaptive Bandit Molecular Dynamics
Rubina1, Syed Tarique Moin1, Shozeb Haider2,3
1Third World Center for Science and Technology, H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
Abstract:
Methionine aminopeptidase-II (MetAP-II) is a metalloprotease, primarily responsible for the cotranslational removal of the N-terminal initiator methionine from the nascent polypeptide chain during protein synthesis. MetAP-II has been implicated in angiogenesis and endothelial cell proliferation and is therefore considered a validated target for cancer therapeutics. However, there is no effective drug available against MetAP-II. In this study, we employ Adaptive Bandit molecular dynamics simulations to investigate the structural dynamics of the apo and ligand-bound MetAP-II. Our results focus on the dynamic behavior of the disordered loop that is not resolved in most of the crystal structures. Further analysis of the conformational flexibility of the disordered loop reveals a hidden cryptic pocket that is predicted to be potentially druggable. The network analysis indicates that the disordered loop region has a direct signaling route to the active site. These findings highlight a new way to target MetAP-II by designing inhibitors for the allosteric site within this disordered loop region.
Insights
Researchers used molecular dynamics to study Methionine aminopeptidase-II (MetAP-II), a cancer target. They discovered a hidden druggable pocket in a disordered loop, suggesting a new therapeutic strategy for cancer.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Methionine aminopeptidase-II (MetAP-II) is a metalloprotease crucial for protein synthesis.
- MetAP-II is implicated in angiogenesis and endothelial cell proliferation, making it a validated cancer therapeutic target.
- Currently, no effective drugs are available to target MetAP-II.
Purpose of the Study:
- To investigate the structural dynamics of apo and ligand-bound MetAP-II.
- To identify potential druggable sites for cancer therapeutics.
Main Methods:
- Adaptive Bandit molecular dynamics simulations were employed.
- Analysis focused on the dynamic behavior of the disordered loop region.
- Network analysis was used to understand signaling pathways.
Main Results:
- The study elucidated the dynamic behavior of MetAP-II's disordered loop.
- A hidden cryptic pocket within the disordered loop was identified and predicted to be druggable.
- Network analysis revealed a direct signaling route from the disordered loop to the active site.
Conclusions:
- The disordered loop of MetAP-II presents a novel allosteric site for drug design.
- Targeting this cryptic pocket could lead to the development of new MetAP-II inhibitors.
- This offers a new therapeutic strategy for cancers involving MetAP-II.
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