8ZM1
Structure of human pyruvate dehydrogenase kinase 2 complexed with compound 6
This is a non-PDB format compatible entry.
Summary for 8ZM1
| Entry DOI | 10.2210/pdb8zm1/pdb |
| Descriptor | [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial, (5~{R})-5-propan-2-ylindeno[1,2-b]pyridin-5-ol (3 entities in total) |
| Functional Keywords | pdhk, kinase inhibitors, fragment screening, pdk1, pdk2, pdk3, pdk4, transferase-inhibitor complex, transferase/inhibitor, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 44873.02 |
| Authors | Akai, S.,Orita, T.,Nomura, A.,Adachi, T. (deposition date: 2024-05-22, release date: 2024-06-19, Last modification date: 2024-07-03) |
| Primary citation | Inoue, M.,Nagamori, H.,Morita, T.,Kobayashi, S.,Suzawa, K.,Kitao, Y.,Saito, T.,Kawahara, I.,Orita, T.,Akai, S.,Adachi, T.,Motomura, T. Design and synthesis of novel fluorene derivatives as inhibitors of pyruvate dehydrogenase kinase. Bioorg.Med.Chem.Lett., 109:129839-129839, 2024 Cited by PubMed Abstract: Activation of pyruvate dehydrogenase (PDH) by inhibition of pyruvate dehydrogenase kinase (PDHK) has the potential for the treatment of diabetes mellitus and its complications, caused by the malfunction of the glycolytic system and glucose oxidation. In this paper, we describe the identification of novel PDHK inhibitors with a fluorene structure. High-throughput screening using our in-house library provided compound 6 as a weak inhibitor that occupied the allosteric lipoyl group binding site in PDHK2. Structure-based drug design (SBDD) while addressing physicochemical properties succeeded in boosting inhibitory activity approximately 700-fold. Thus obtained compound 32 showed favorable pharmacokinetics profiles supported by high membrane permeability and metabolic stability, and exhibited activation of PDH in rat livers and a glucose lowering effect in Zucker fatty rats. PubMed: 38844173DOI: 10.1016/j.bmcl.2024.129839 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.35 Å) |
Structure validation
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