5JFR

Potent, Reversible MetAP2 Inhibitors via Fragment Based Drug Discovery

5JFR の概要

• エントリーDOI: 10.2210/pdb5jfr/pdb
• 関連するPDBエントリー: 5JHU 5JI6
• 分子名称: Methionine aminopeptidase 2, MANGANESE (II) ION, DIMETHYL SULFOXIDE, ... (6 entities in total)
• 機能のキーワード: hydrolase, peptidase, metal ion binding, proteolysis, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm : P50579
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 41912.35

構造登録者

Dougan, D.R.,Lawson, J.D. (登録日: 2016-04-19, 公開日: 2016-05-25, 最終更新日: 2024-11-13)

主引用文献

McBride, C.,Cheruvallath, Z.,Komandla, M.,Tang, M.,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 2.
Bioorg.Med.Chem.Lett., 26:2779-2783, 2016

PubMed Abstract: Methionine aminopeptidase-2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. This step is required before they will fold or function correctly. Pre-clinical and clinical studies with a MetAP2 inhibitor suggest that they could be used as a novel treatment for obesity. Herein we describe the discovery of a series of pyrazolo[4,3-b]indoles as reversible MetAP2 inhibitors. A fragment-based drug discovery (FBDD) approach was used, beginning with the screening of fragment libraries to generate hits with high ligand-efficiency (LE). An indazole core was selected for further elaboration, guided by structural information. SAR from the indazole series led to the design of a pyrazolo[4,3-b]indole core and accelerated knowledge-based fragment growth resulted in potent and efficient MetAP2 inhibitors, which have shown robust and sustainable body weight loss in DIO mice when dosed orally.

PubMed: 27136719
DOI: 10.1016/j.bmcl.2016.04.072

実験手法

X-RAY DIFFRACTION (1.6 Å)