4qia | pdb_00004qia
Crystal structure of human insulin degrading enzyme (ide) in complex with inhibitor N-benzyl-N-(carboxymethyl)glycyl-L-histidine
Structural highlights
Function[IDE_HUMAN] Plays a role in the cellular breakdown of insulin, IAPP, glucagon, bradykinin, kallidin and other peptides, and thereby plays a role in intercellular peptide signaling. Degrades amyloid formed by APP and IAPP. May play a role in the degradation and clearance of naturally secreted amyloid beta-protein by neurons and microglia.[1] [2] [3] Publication Abstract from PubMedInsulin degrading enzyme (IDE) is a zinc metalloprotease that degrades small amyloid peptides such as amyloid-a and insulin. So far the dearth of IDE-specific pharmacological inhibitors impacts the understanding of its role in the physiopathology of Alzheimer's disease, amyloid-a clearance, and its validation as a potential therapeutic target. Hit 1 was previously discovered by high-throughput screening. Here we describe the structure-activity study, that required the synthesis of 48 analogues. We found that while the carboxylic acid, the imidazole and the tertiary amine were critical for activity, the methyl ester was successfully optimized to an amide or a 1,2,4-oxadiazole. Along with improving their activity, compounds were optimized for solubility, lipophilicity and stability in plasma and microsomes. The docking or co-crystallization of some compounds at the exosite or the catalytic site of IDE provided the structural basis for IDE inhibition. The pharmacokinetic properties of best compounds 44 and 46 were measured in vivo. As a result, 44 (BDM43079) and its methyl ester precursor 48 (BDM43124) are useful chemical probes for the exploration of IDE's role. Structure-activity relationships of imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, dual binders of human insulin-degrading enzyme.,Charton J, Gauriot M, Totobenazara J, Hennuyer N, Dumont J, Bosc D, Marechal X, Elbakali J, Herledan A, Wen X, Ronco C, Gras-Masse H, Heninot A, Pottiez V, Landry V, Staels B, Liang WG, Leroux F, Tang WJ, Deprez B, Deprez-Poulain R Eur J Med Chem. 2015 Jan 27;90:547-67. doi: 10.1016/j.ejmech.2014.12.005. Epub, 2014 Dec 4. PMID:25489670[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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