7EBH

Crystal structure of human pyruvate dehydrogenase kinase 2 in complex with compound 13

7EBH の概要

• エントリーDOI: 10.2210/pdb7ebh/pdb
• 関連するPDBエントリー: 7EA0 7EAS 7EAT 7EBB 7EBG
• 分子名称: [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial, CHLORIDE ION, ACETATE ION, ... (6 entities in total)
• 機能のキーワード: pdhk, kinase inhibitors, fragment screening, pdk1, pdk2, pdk3, pdk4, 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: 45211.66

構造登録者

Orita, T.,Doi, S.,Iwanaga, T.,Adachi, T. (登録日: 2021-03-09, 公開日: 2021-08-04, 最終更新日: 2023-11-29)

主引用文献

Akaki, T.,Bessho, Y.,Ito, T.,Fujioka, S.,Ubukata, M.,Mori, G.,Yamanaka, K.,Orita, T.,Doi, S.,Iwanaga, T.,Ikegashira, K.,Hantani, Y.,Nakanishi, I.,Adachi, T.
Fragment-based lead discovery to identify novel inhibitors that target the ATP binding site of pyruvate dehydrogenase kinases.
Bioorg.Med.Chem., 44:116283-116283, 2021

PubMed Abstract: A fragment-based lead discovery approach was applied to Pyruvate Dehydrogenase Kinases (PDHKs) to discover inhibitors against the ATP binding site with novel chemotypes. X-ray fragment screening toward PDHK4 provided a fragment hit 1 with a characteristic interaction in a deep pocket of the ATP binding site. While known inhibitors utilize several water molecules in a deep pocket to form water-mediated hydrogen bond interactions, the fragment hit binds deeper in the pocket with a hydrophobic group. Displacement of a remaining water molecule in the pocket led to the identification of lead compound 7 with a notable improvement in inhibition potency. This lead compound possessed high ligand efficiency (LE) and showed decent selectivity profile. Two additional lead compounds 10 and 13 with new scaffolds with tricyclic and bicyclic cores were generated by merging structural information of another fragment hit 2. The characteristic interaction of these novel inhibitors in a deep pocket provides new structural insights about PDHKs ATP binding site and opens a novel direction for the development of PDHKs inhibitors.

PubMed: 34274549
DOI: 10.1016/j.bmc.2021.116283

実験手法

X-RAY DIFFRACTION (1.96 Å)