In silico screening identifies a novel potential PARP1 inhibitor targeting synthetic lethality in cancer treatment

Jian Li*, Nan Zhou, Peiling Cai, Jinku Bao

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)
12 Downloads (Pure)

Abstract

Synthetic lethality describes situations in which defects in two different genes or pathways together result in cell death. This concept has been applied to drug development for cancer treatment, as represented by Poly (ADP-ribose) polymerase (PARPs) inhibitors. In the current study, we performed a computational screening to discover new PARP inhibitors. Among the 11,247 compounds analyzed, one natural product, ZINC67913374, stood out by its superior performance in the simulation analyses. Compared with the FDA approved PARP1 inhibitor, olaparib, our results demonstrated that the ZINC67913374 compound achieved a better grid score (_86.8) and amber score (-51.42). Molecular dynamics simulations suggested that the PARP1-ZINC67913374 complex was more stable than olaparib. The binding free energy for ZINC67913374 was -177.28 kJ/mol while that of olaparib was -159.16 kJ/mol. These results indicated ZINC67913374 bound to PARP1 with a higher affinity, which suggest ZINC67913374 has promising potential for cancer drug development.

Original languageEnglish
Article number258
Pages (from-to)1-11
Number of pages11
JournalInternational Journal of Molecular Sciences
Volume17
Issue number2
DOIs
Publication statusPublished - 19 Feb 2016
Externally publishedYes

Bibliographical note

Copyright the Author(s) 2016. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • synthetic lethality
  • PARP inhibitor
  • DNA damage response (DDR)

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