Discovery of Keap1−Nrf2 small−molecule inhibitors from phytochemicals based on molecular docking

Abstract

Various phytochemicals have been reported to protect against oxidative stress. However, the mechanism underlying has not been systematically evaluated, which limited their application in disease treatment. Nuclear factor erythroid 2−related factor 2 (Nrf2), a central transcription factor in oxidative stress response related to numerous diseases, is activated after dissociating from the cytoskeleton−anchored Kelch−like ECH−associated protein 1 (Keap1). The Keap1-Nrf2 protein-protein interaction has become an important drug target. This study was designed to clarify whether antioxidantive phytochemicals inhibit the Keap1-Nrf2 protein-protein interaction and activate the Nrf2-ARE signaling pathway efficiently. Molecular docking and 3D−QSAR were applied to evaluate the interaction effects between 178 antioxidant phytochemicals and the Nrf2 binding site in Keap1.The Nrf2 activation effect was tested on a H 2 O 2 −induced oxidative−injured cell model. Results showed that the 178 phytochemicals could be divided into high−, medium−, and low−total−score groups depending on their binding affinity with Keap1, and the high−total−score group consisted of 24 compounds with abundant oxygen or glycosides. Meanwhile, these compounds could bind with key amino acids in the structure of the Keap1−Nrf2 interface. Compounds from high−total−score group show effective activation effects on Nrf2. In conclusion, phytochemicals showed high binding affinity with Keap1 are promising new Nrf2 activators.

Natural compounds against doxorubicin‐induced cardiotoxicity: A review on the involvement of Nrf2/ARE signaling pathway

“…Wang et al, 2012). NARG can effectively inhibit the interaction between Nrf2 with Keap1 (M. Li, Huang, et al, 2019). Han et al indicated that NARG pretreatment induced ERK, Nrf2, and NQO1…”

“…NARG possesses anti‐microbial, anti‐viral, anti‐inflammatory, anti‐oxidant, and anti‐cancer activities (J. Wang et al, 2012). NARG can effectively inhibit the interaction between Nrf2 with Keap1 (M. Li, Huang, et al, 2019). Han et al indicated that NARG pretreatment induced ERK, Nrf2, and NQO1 protein levels in DOX‐treated cardiomyocytes.…”

The Cytoprotective Activity of Nrf2 Is Regulated by Phytochemicals (Sulforaphane, Curcumin, and Silymarin)

“…Moreover, Li et al suggested that phenylethanoid glycosides, tocopherols, flavones, flavanols, anthocyanins, and flavonols can act as inhibitors of its inactivating action on Nrf2, subsequently triggering higher Nrf2 protective activity [208].…”

Flavolignans from Silymarin as Nrf2 Bioactivators and Their Therapeutic Applications

“…Recent works describe the action of compounds on this system by direct interaction or by the disruption of proteins linked to Nrf2 activity [166,167], with Keap1 as the main target [168],due to that, under basal conditions, the Nrf2 protein is constitutively trapped by Keap1 and retained in the cytoplasm for ubiquitin conjugation and subsequent proteasome degradation. In this regard, 178 phytochemicals proven to possess good antioxidant properties were selected and tested in silico by Li et al, suggesting that phenylethanoid glycosides, tocopherols, flavones, flavanols, anthocyanins, and flavonols have entertained high affinity with Keap1 and have potential as inhibitors of the inactivator action on Nrf2 [169]. In a complementary manner, itis noteworthy that several research workgroups have developed and tested compounds to disrupt Keap1:Nrf2 interaction [168,170,171].…”