Discovery of NAD(P)H:quinone oxidoreductase 1 (NQO1) inhibitors with novel chemical scaffolds by shape-based virtual screening combined with cascade docking

Abstract

A number of novel NAD(P)H:quinone oxidoreductase 1 (NQO1) inhibitors were discovered from the ChmeDiv database via a simple protocol. Based on two reference NQO1 inhibitors, dicoumarol (DIC) and ES936, shape-based similarity search and cascade docking filtering were conducted to identify new NQO1 inhibitors. Using these techniques, 43 compounds were selected, ordered, and tested. Among them, 7 compounds with novel chemical scaffolds were confirmed to be active by in vitro assays. Determination of the ability for protecting against NQO1-mediated toxicity of β-lapachone (β-lap) confirmed that compounds 8, 10 and 13 may be pharmacological useful for probing the function of NQO1 in cells. Fig. 1 Representative structures of known inhibitors of NQO1.Fig. 10 A549 cells were treated for 2 h with β-lap and 30 µmol•L -1 of the compounds. The toxicity was determined 72 h later by the MTT assay.

NAD(P)H:Quinone Oxidoreductase 1 (NQO1) as a Therapeutic and Diagnostic Target in Cancer

“…In the case of DIC ( 2 ) and ES936 ( 6 ), a better understanding of NQO1’s biological functions requires some new scaffolds for NQO1 inhibitors. Using compounds 2 and 6 for reference, Bian et al recently identified compounds 9 – 11 with different chemical scaffolds as NQO1 inhibitors with IC 50 values of 0.92, 2.04, and 1.47 μM, respectively, through a shape-based similarity search and a second cascade docking filtering. By comparing the docked pose of 9 within the NQO1 active site to that of 2 , it was found that the general molecular orientation and the spatial location of 2 and 9 are very similar, and the modifications of fragments A and C in 9 possibly increased its affinity toward NQO1 .…”

An NAD(P)H:Quinone Oxidoreductase 1 Responsive and Self-Immolative Prodrug of 5-Fluorouracil for Safe and Effective Cancer Therapy

“…Thus, 1 has a wide therapeutic window and exhibits reduced toxicity to normal tissues; this prodrug would benefit from further research on its potential as a specific cancer therapy. Additionally, as an NQO1-responsive prodrug, 1 is expected to be promising in personalized chemotherapy for NQO1-overexpressing cancers when combined with NQO1 diagnostic reagents. , …”

The Influence of Brazilian Biodiversity on Searching for Human Use Pharmaceuticals

“…However, Arqule reports that it is a prodrug of β-lapachone. Recently a Chinese group published data on modifications of the base structure that might lead to drug entities with better pharmacological activities, 83 with compound 3k (31) being their best molecule from a solubility and stability aspect. 84 These two papers should be consulted by readers interested in how an initial structure from the late 1890s, may lead to novel pharmaceuticals around a 130 years later.…”