8ZM2

Structure of human pyruvate dehydrogenase kinase 2 complexed with compound 16

これはPDB形式変換不可エントリーです。

8ZM2 の概要

• エントリーDOI: 10.2210/pdb8zm2/pdb
• 分子名称: [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial, methyl (9~{R})-9-oxidanyl-9-(trifluoromethyl)fluorene-4-carboxylate (3 entities in total)
• 機能のキーワード: pdhk, kinase inhibitors, fragment screening, pdk1, pdk2, pdk3, pdk4, transferase-inhibitor complex, transferase/inhibitor, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 44955.98

構造登録者

Akai, S.,Orita, T.,Nomura, A.,Adachi, T. (登録日: 2024-05-22, 公開日: 2024-06-19, 最終更新日: 2024-07-03)

主引用文献

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

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: 38844173
DOI: 10.1016/j.bmcl.2024.129839

実験手法

X-RAY DIFFRACTION (2.34 Å)