Allosteric site in MetAP-II explored by Markov State model-based adaptive sampling molecular dynamics simulation Rubina 1 , Syed Tarique Moin 1 , and Shozeb Haider 2 1 Third World Center for Science and Technology, University of Karachi, Pakistan, 2 UCL School of Pharmacy, London, UK Methionine aminopeptidase-II is a metalloprotease, primarily responsible for the co-translational removal of N-terminal initiator methionine from the nascent polypeptide chain during protein synthesis 1 . MetAP-II has been involved in angiogenesis and endothelial cell proliferation which ultimately is considered a target of angiogenesis and cancer 2 . Therefore, inhibition of MetAP-II could be a new therapeutic approach for the treatment of cancer. However, there is no effective drug available for cancer involving MetAP-II. Here, by combining Markov State Model-based Adaptive Sampling molecular dynamics simulations to ligand-free and ligand-bound MetAP-II along with small molecule ring fragments screening on metastable states, we revealed the allosteric behavior of the disordered loop region that is missing in most of the crystal structures. This loop region has a direct signal to the binding site and follows a single route. Further analysis using different tools confirms the druggability of the pocket that formed due to this loop region. These findings explored the new way for MetAP-II inhibition by designing inhibitors for the allosteric loop region. References 1. Morgen, M.; Jost, C.; Malz, M.; Janowski, R.; Niessing, D.; Klein, C. D.; Gunkel, N.; Miller, A. K. Spiroepoxytriazoles are fumagillin-like irreversible inhibitors of metap2 with potent cellular activity. ACS Chemical Biology 2016, 11(4), 1001–1011. 2. Grochot-Przeczek, A.; Kozakowska, M.; Dulak, J.; Jozkowicz, A. Endothelial cell origin, differentiation, heterogeneity and function. Angiogenesis and Vascularisation: Cellular and Molecular Mechanisms in Health and Diseases 2013, pp 3–26.
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