Identification of a Cryptic Pocket in Methionine Aminopeptidase-II Using Adaptive Bandit Molecular Dynamics Simulations and Markov State Models.
| Autor: | Rubina; Third 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., Moin ST; Third 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., Haider S; UCL School of Pharmacy, University College London, London WC1N 1AX, U.K.; UCL Centre for Advanced Research Computing, University College London, London WC1H 9RN, U.K. |
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| Jazyk: | angličtina |
| Zdroj: | ACS omega [ACS Omega] 2024 Jun 18; Vol. 9 (26), pp. 28534-28545. Date of Electronic Publication: 2024 Jun 18 (Print Publication: 2024). |
| DOI: | 10.1021/acsomega.4c02516 |
| Abstrakt: | 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. Competing Interests: The authors declare no competing financial interest. (© 2024 The Authors. Published by American Chemical Society.) |
| Databáze: | MEDLINE |
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