6QEG
CRYSTAL STRUCTURE OF HUMAN METHIONINE AMINOPEPTIDASE-2 IN COMPLEX WITH AN INHIBITOR 2-Oxo-1-phenyl-pyrrolidine-3-carboxylic acid (2-thiophen-2-yl-ethyl)-amide
Summary for 6QEG
| Entry DOI | 10.2210/pdb6qeg/pdb |
| Descriptor | Methionine aminopeptidase 2, GLYCEROL, (3~{S})-3-oxidanyl-2-oxidanylidene-1-phenyl-~{N}-(2-thiophen-2-ylethyl)pyrrolidine-3-carboxamide, ... (5 entities in total) |
| Functional Keywords | hydrolase, peptidase, metal ion binding, proteolysis, hydrolase-hydrolase inhibitor complex |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 43002.58 |
| Authors | Musil, D.,Heinrich, T.,Lehmann, M. (deposition date: 2019-01-07, release date: 2019-05-01, Last modification date: 2024-05-15) |
| Primary citation | Heinrich, T.,Seenisamy, J.,Blume, B.,Bomke, J.,Calderini, M.,Eckert, U.,Friese-Hamim, M.,Kohl, R.,Lehmann, M.,Leuthner, B.,Musil, D.,Rohdich, F.,Zenke, F.T. Discovery and Structure-Based Optimization of Next-Generation Reversible Methionine Aminopeptidase-2 (MetAP-2) Inhibitors. J.Med.Chem., 62:5025-5039, 2019 Cited by PubMed Abstract: Co- and post-translational processing are crucial maturation steps to generate functional proteins. MetAP-2 plays an important role in this process, and inhibition of its proteolytic activity has been shown to be important for angiogenesis and tumor growth, suggesting that small-molecule inhibitors of MetAP-2 may be promising options for the treatment of cancer. This work describes the discovery and structure-based hit optimization of a novel MetAP-2 inhibitory scaffold. Of critical importance, a cyclic tartronic diamide coordinates the MetAP-2 metal ion in the active site while additional side chains of the molecule were designed to occupy the lipophilic methionine side chain recognition pocket as well as the shallow cavity at the opening of the active site. The racemic screening hit from HTS campaign 11a was discovered with an enzymatic IC of 150 nM. The resynthesized eutomer confirmed this activity and inhibited HUVEC proliferation with an IC of 1.9 μM. Its structural analysis revealed a sophisticated interaction pattern of polar and lipophilic contacts that were used to improve cellular potency to an IC of 15 nM. In parallel, the molecular properties were optimized on plasma exposure and antitumor efficacy which led to the identification of advanced lead 21. PubMed: 30939017DOI: 10.1021/acs.jmedchem.9b00041 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.08 Å) |
Structure validation
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