Targeting Human Poly(ADP-Ribose) Polymerase-1 with Natural Medicines and Its Potential Applications in Ovarian Cancer Therapeutics

Archiv der Pharmazie
Min SongShi-Feng Kan

Abstract

Targeting poly(ADP-ribose) polymerase-1 (PARP-1) has been established as an efficient therapeutics for advanced ovarian cancer. In this study, we describe an integrated procedure that combines virtual computer screening and an experimental enzyme assay to discover novel potent PARP-1 inhibitors from more than 130000 commercially available natural products. The protocol employed a stepwise strategy to fast exclude typical PARP-1 non-binders and then performing rigorous prediction to identify promising candidates with high potency against PARP-1. Consequently, eight natural products were hit and tested to determine their inhibitory activities against the PARP-1 catalytic domain. From these, four compounds, i.e., puerarin, phloretin, chlorogenic acid, and biochanin A, were found to have high or moderate potencies with inhibitory IC50 values of 6, 470, 25, and 86 nM, respectively. The values are comparable to that (IC50  = 1.94 nM) of the FDA-approved agent olaparib. Structural and energetic analyses of the modeled structures of the PARP-1 catalytic domain complexed with the newly identified inhibitors revealed a common binding mode in the complexes: the active site of PARP-1 is composed of a thin polar helix and a flat non-polar p...Continue Reading

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Citations

Nov 15, 2016·Expert Opinion on Therapeutic Patents·Zigao YuanYuyang Jiang
Nov 2, 2018·Chemical Biology & Drug Design·Angamba Meetei PotshangbamVaibhav Vindal
Feb 29, 2020·Anti-cancer Agents in Medicinal Chemistry·Manikanta MurahariVasanti Suvarna

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