# Discovery of novel and potent celastrol derivatives as PRDX1 inhibitors for cancer therapy through structure-based virtual screening

## TL;DR

Researchers discovered a potent new compound, CP1, that inhibits PRDX1, an antioxidant enzyme in cancer cells, showing strong antitumor effects without harming normal cells.

## Contribution

The study introduces CP1, a novel and highly potent celastrol derivative, as a selective PRDX1 inhibitor with low toxicity and high antiproliferative activity.

## Key findings

- CP1 inhibited PRDX1 with an IC50 of 0.08 ± 0.01 nM, showing high potency.
- CP1 exhibited strong antiproliferative effects on A549, HepG2, and MCF-7 tumor cells.
- CP1 showed no significant hepatotoxicity or renal toxicity in mice.

## Abstract

Peroxiredoxin 1 (PRDX1) is an antioxidant enzyme overexpressed in several cancers that protects tumor cells from oxidative damage by scavenging excess reactive oxygen species making it a potential strategy for cancer therapy.

In this study, a multi-step screening strategy combining molecular docking, enzyme inhibition assay, enzyme kinetic studies, molecular dynamics (MD) simulations, MST assays, MTT assays and in vivo toxicity assay was used to discover PRDX1 inhibitors.

Five compounds (CPs 1–5) targeting PRDX1 were identified through molecular docking screening. CPs 1-5 showed significant PRDX1 inhibition at the nanomolar level. Among them, CP1 exhibited the most potent inhibitory activity (IC50 = 0.08 ± 0.01 nM) and high selectivity against PRDX1. The kinetic study showed that CP1 acted as noncompetitive PRDX1 inhibitor. MD simulations confirmed the stability of the CP1-PRDX1 complex. MST assays revealed that CP1 displayed a significant binding affinity for PRDX1 (K
d = 0.06 ± 0.001 nM). Importantly, CP1 exhibited significant antiproliferative effects on A549, HepG2 and MCF-7 tumor cells without toxicity to other normal cells. Meanwhile, CP1 did not exhibit significant hepatotoxicity or renal toxicity in mice.

The results suggest that CP1 is a promising antitumor candidate for cancer therapy and merits further investigation.