8HUB

AMP deaminase 2 in complex with an inhibitor

8HUB の概要

• エントリーDOI: 10.2210/pdb8hub/pdb
• 関連するPDBエントリー: 8HU6
• 分子名称: AMP deaminase 2, ZINC ION, 3,3-dimethyl-4-(phenylmethyl)-2~{H}-quinoxaline-1-carboxamide (3 entities in total)
• 機能のキーワード: complex, deaminase, amp, imp, energy metabolism, inhibitor, allosteric inhibitor, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 316158.36

構造登録者

Adachi, T.,Doi, S. (登録日: 2022-12-23, 公開日: 2023-01-18, 最終更新日: 2024-05-29)

主引用文献

Kitao, Y.,Saito, T.,Watanabe, S.,Ohe, Y.,Takahashi, K.,Akaki, T.,Adachi, T.,Doi, S.,Yamanaka, K.,Murai, Y.,Oba, M.,Suzuki, T.
The discovery of 3,3-dimethyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamides as AMPD2 inhibitors with a novel mechanism of action.
Bioorg.Med.Chem.Lett., 80:129110-129110, 2023

PubMed Abstract: AMP deaminase 2 (AMPD2) has been thought to play an important role in energy homeostasis and immuno-oncology, while selective AMPD2 inhibitors are highly demanded to clarify the physiological function of AMPD2. In this report, we describe selective AMPD2 inhibitors inducing allosteric modulation. Based on hypothesis that compounds that exhibit increased inhibition by preincubation would cause conformational change of the enzyme, starting from HTS hit compound 4, we discovered compound 8 through the SAR study. From X-ray structural information of 8, this chemical series has a novel mechanism of action that changes the substrate pocket to prevent AMP from binding. Further elaboration of compound 8 led to the tool compound 21 which exhibited potent inhibitory activity of AMPD2 in ex vivo evaluation of mouse liver.

PubMed: 36563792
DOI: 10.1016/j.bmcl.2022.129110

実験手法

X-RAY DIFFRACTION (3.25 Å)