5JI6

Potent, Reversible MetAP2 Inhibitors via FBDD

Summary for 5JI6

• Entry DOI: 10.2210/pdb5ji6/pdb
• Related: 5JFR 5JHU
• Descriptor: Methionine aminopeptidase 2, MANGANESE (II) ION, SULFATE ION, ... (5 entities in total)
• Functional Keywords: hydrolase, peptidase, metal ion binding, proteolysis, hydrolase4-hydrolase inhibitor complex, hydrolase4/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : P50579
• Total number of polymer chains: 1
• Total formula weight: 41839.16

Authors

Dougan, D.R.,Lawson, J.D. (deposition date: 2016-04-21, release date: 2016-05-25, Last modification date: 2024-11-06)

Primary citation

Cheruvallath, Z.,Tang, M.,McBride, C.,Komandla, M.,Miura, J.,Ton-Nu, T.,Erikson, P.,Feng, J.,Farrell, P.,Lawson, J.D.,Vanderpool, D.,Wu, Y.,Dougan, D.R.,Plonowski, A.,Holub, C.,Larson, C.
Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design-Part 1.
Bioorg.Med.Chem.Lett., 26:2774-2778, 2016

PubMed Abstract: Methionine aminopeptidase 2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. Pre-clinical and clinical studies suggest that MetAP2 inhibitors could be used as a novel treatment for obesity. Herein we describe our use of fragment screening methods and structural biology to quickly identify and elaborate an indazole fragment into a series of reversible MetAP2 inhibitors with <10nM potency, excellent selectivity, and favorable in vitro safety profiles.

PubMed: 27155900
DOI: 10.1016/j.bmcl.2016.04.073

Experimental method

X-RAY DIFFRACTION (2.15 Å)