Developing Inhibitors of the p47phox-p22phox Protein-Protein Interaction by Fragment-Based Drug Discovery.,Journal of Medicinal Chemistry

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Developing Inhibitors of the p47phox-p22phox Protein-Protein Interaction by Fragment-Based Drug Discovery.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-01-23 , DOI: 10.1021/acs.jmedchem.9b01492
Sara Marie Øie Solbak ₁ , Jie Zang ₁ , Dilip Narayanan ₁ , Lars Jakobsen Høj ₁ , Saskia Bucciarelli ₁ , Charlotte Softley _{2,

3} , Sebastian Meier ₄ , Annette Eva Langkilde ₁ , Charlotte Held Gotfredsen ₄ , Michael Sattler _{2,

3} , Anders Bach ₁

Affiliation

Nicotinamide adenine dinucleotide phosphate oxidase isoform 2 is an enzyme complex, which generates reactive oxygen species and contributes to oxidative stress. The p47phox-p22phox interaction is critical for the activation of the catalytical NOX2 domain, and p47phox is a potential target for therapeutic intervention. By screening 2500 fragments using fluorescence polarization and a thermal shift assay and validation by surface plasmon resonance, we found eight hits toward the tandem SH3 domain of p47phox (p47phoxSH3A-B) with KD values of 400-600 μM. Structural studies revealed that fragments 1 and 2 bound two separate binding sites in the elongated conformation of p47phoxSH3A-B and these competed with p22phox for binding to p47phoxSH3A-B. Chemical optimization led to a dimeric compound with the ability to potently inhibit the p47phoxSH3A-B-p22phox interaction (Ki of 20 μM). Thereby, we reveal a new way of targeting p47phox and present the first report of drug-like molecules with the ability to bind p47phox and inhibit its interaction with p22phox.

中文翻译：

通过基于片段的药物发现开发的p47phox-p22phox蛋白-蛋白质相互作用的抑制剂。

烟酰胺腺嘌呤二核苷酸磷酸氧化酶同工型2是一种酶复合物，可产生活性氧并有助于氧化应激。p47phox-p22phox相互作用对于催化NOX2结构域的激活至关重要，而p47phox是治疗干预的潜在靶标。通过使用荧光偏振和热位移分析筛选2500个片段并通过表面等离振子共振进行验证，我们发现p47phox（p47phoxSH3A-B）的串联SH3域有8个命中点，KD值为400-600μM。结构研究表明，片段1和片段2结合了p47phoxSH3A-B延长构象中的两个单独的结合位点，这些位点与p22phox竞争与p47phoxSH3A-B的结合。化学优化产生了一种二聚体化合物，具有有效抑制p47phoxSH3A-B-p22phox相互作用的能力（Ki为20μM）。因此，我们揭示了靶向p47phox的新方法，并首次报道了具有结合p47phox并抑制其与p22phox相互作用的药物样分子的能力。

更新日期：2020-01-23

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