8HUB
AMP deaminase 2 in complex with an inhibitor
Summary for 8HUB
| Entry DOI | 10.2210/pdb8hub/pdb |
| Related | 8HU6 |
| Descriptor | AMP deaminase 2, ZINC ION, 3,3-dimethyl-4-(phenylmethyl)-2~{H}-quinoxaline-1-carboxamide (3 entities in total) |
| Functional Keywords | complex, deaminase, amp, imp, energy metabolism, inhibitor, allosteric inhibitor, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 316158.36 |
| Authors | Adachi, T.,Doi, S. (deposition date: 2022-12-23, release date: 2023-01-18, Last modification date: 2024-05-29) |
| Primary citation | 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 Cited by 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: 36563792DOI: 10.1016/j.bmcl.2022.129110 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.25 Å) |
Structure validation
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