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Int. J. Mol. Sci. 2016, 17(2), 258; doi:10.3390/ijms17020258

In Silico Screening Identifies a Novel Potential PARP1 Inhibitor Targeting Synthetic Lethality in Cancer Treatment

1,†,* , 2,†
,
1
and
2,*
1
School of Medicine, Chengdu University, Chengdu 610106, China
2
College of Life Sciences and Key Laboratory for Bio-Resources of Ministry of Education, Sichuan University, Chengdu 610064, China
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editor: Ge Zhang
Received: 24 December 2015 / Revised: 5 February 2016 / Accepted: 6 February 2016 / Published: 19 February 2016
View Full-Text   |   Download PDF [1268 KB, uploaded 19 February 2016]   |  

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. View Full-Text
Keywords: synthetic lethality; PARP inhibitor; DNA damage response (DDR) synthetic lethality; PARP inhibitor; DNA damage response (DDR)
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Li, J.; Zhou, N.; Cai, P.; Bao, J. In Silico Screening Identifies a Novel Potential PARP1 Inhibitor Targeting Synthetic Lethality in Cancer Treatment. Int. J. Mol. Sci. 2016, 17, 258.

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