6JVP

Crystal structure of human MTH1 in complex with compound MI1024

6JVP の概要

• エントリーDOI: 10.2210/pdb6jvp/pdb
• 分子名称: 7,8-dihydro-8-oxoguanine triphosphatase, N4-cyclopropyl-6-piperidin-1-yl-pyrimidine-2,4-diamine (3 entities in total)
• 機能のキーワード: mth1, oxidative dna damage, 8-oxo-dgtp, inhibitor development, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 36409.55

構造登録者

Peng, C.,Li, Y.H.,Cheng, Y.S. (登録日: 2019-04-17, 公開日: 2020-10-28, 最終更新日: 2024-03-27)

主引用文献

Peng, C.,Li, Y.H.,Yu, C.W.,Cheng, Z.H.,Liu, J.R.,Hsu, J.L.,Hsin, L.W.,Huang, C.T.,Juan, H.F.,Chern, J.W.,Cheng, Y.S.
Inhibitor development of MTH1 via high-throughput screening with fragment based library and MTH1 substrate binding cavity.
Bioorg.Chem., 110:104813-104813, 2021

PubMed Abstract: MutT Homolog 1 (MTH1) has been proven to hydrolyze oxidized nucleotide triphosphates during DNA repair. It can prevent the incorporation of wrong nucleotides during DNA replication and mitigate cell apoptosis. In a cancer cell, abundant reactive oxygen species can lead to substantial DNA damage and DNA mutations by base-pairing mismatch. MTH1 could eliminate oxidized dNTP and prevent cancer cells from entering cell death. Therefore, inhibition of MTH1 activity is considered to be an anti-cancer therapeutic target. In this study, high-throughput screening techniques were combined with a fragment-based library containing 2,313 compounds, which were used to screen for lead compounds with MTH1 inhibitor activity. Four compounds with MTH1 inhibitor ability were selected, and compound MI0639 was found to have the highest effective inhibition. To discover the selectivity and specificity of this action, several derivatives based on the MTH1 and MI0639 complex structure were synthesized. We compared 14 complex structures of MTH1 and the various compounds in combination with enzymatic inhibition and thermodynamic analysis. Nanomolar-range IC inhibition abilities by enzyme kinetics and K values by thermodynamic analysis were obtained for two compounds, named MI1020 and MI1024. Based on structural information and compound optimization, we aim to provide a strategy for the development of MTH1 inhibitors with high selectivity and specificity.

PubMed: 33774493
DOI: 10.1016/j.bioorg.2021.104813

実験手法

X-RAY DIFFRACTION (2.206 Å)