Fragment-growing guided design of Keap1-Nrf2 protein-protein interaction inhibitors for targeting myocarditis.

Fragment-growing guided design of Keap1-Nrf2 protein-protein interaction inhibitors for targeting myocarditis.
Free Radic Biol Med. 2018 Feb 08;:
Authors: Meng N, Tang H, Zhang H, Jiang C, Su L, Min X, Zhang W, Zhang H, Miao Z, Zhang W, Zhuang C
Abstract
Small-molecule inhibitors that block the Keap1-Nrf2 protein-protein interactions are being intensely pursued as a new therapeutic strategy for oxidative stress-related diseases, such as cancer, diabetes, Alzheimer's disease, arteriosclerosis, inflammation and myocarditis. However, there are not enough studies on antioxidant treatments using small molecules in myocarditis. We herein provided a series of novel hydronaphthoquinones as the Keap1-Nrf2 interaction inhibitors targeting LPS-induced myocarditis both in vitro and in vivo. These compounds were designed through an in-silico fragment growing approach based on our previous reported compound, S47 (1). The new compounds were predicted to form additional hydrogen bonds with the S363 residue, leading to higher inhibitory activity. Among these new derivatives, compounds S01 and S05 emerged as inhibitors with significant biochemical potency, as determined by fluorescent anisotropy assay and confirmed by surface plasmon resonance (SPR) and differential scanning fluorimetry (DSF) assays. These inhibitors can dose-dependently protect the H9c2 cardiac cells against LPS-induced injury (100% at 2μM and 4μM) and effectively prolong survival ...

Source: Free Radical Biology and Medicine - February 8, 2018 Category: Biology Authors: Meng N, Tang H, Zhang H, Jiang C, Su L, Min X, Zhang W, Zhang H, Miao Z, Zhang W, Zhuang C Tags: Free Radic Biol Med Source Type: research