Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Li, Jian, Zhou, Nan, Cai, Peiling, Bao, Jinku
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783987/
https://www.ncbi.nlm.nih.gov/pubmed/26907257
http://dx.doi.org/10.3390/ijms17020258
_version_ 1782420193742422016
author Li, Jian
Zhou, Nan
Cai, Peiling
Bao, Jinku
author_facet Li, Jian
Zhou, Nan
Cai, Peiling
Bao, Jinku
author_sort Li, Jian
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4783987
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-47839872016-03-14 In Silico Screening Identifies a Novel Potential PARP1 Inhibitor Targeting Synthetic Lethality in Cancer Treatment Li, Jian Zhou, Nan Cai, Peiling Bao, Jinku Int J Mol Sci Article 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. MDPI 2016-02-19 /pmc/articles/PMC4783987/ /pubmed/26907257 http://dx.doi.org/10.3390/ijms17020258 Text en © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Li, Jian
Zhou, Nan
Cai, Peiling
Bao, Jinku
In Silico Screening Identifies a Novel Potential PARP1 Inhibitor Targeting Synthetic Lethality in Cancer Treatment
title In Silico Screening Identifies a Novel Potential PARP1 Inhibitor Targeting Synthetic Lethality in Cancer Treatment
title_full In Silico Screening Identifies a Novel Potential PARP1 Inhibitor Targeting Synthetic Lethality in Cancer Treatment
title_fullStr In Silico Screening Identifies a Novel Potential PARP1 Inhibitor Targeting Synthetic Lethality in Cancer Treatment
title_full_unstemmed In Silico Screening Identifies a Novel Potential PARP1 Inhibitor Targeting Synthetic Lethality in Cancer Treatment
title_short In Silico Screening Identifies a Novel Potential PARP1 Inhibitor Targeting Synthetic Lethality in Cancer Treatment
title_sort in silico screening identifies a novel potential parp1 inhibitor targeting synthetic lethality in cancer treatment
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783987/
https://www.ncbi.nlm.nih.gov/pubmed/26907257
http://dx.doi.org/10.3390/ijms17020258
work_keys_str_mv AT lijian insilicoscreeningidentifiesanovelpotentialparp1inhibitortargetingsyntheticlethalityincancertreatment
AT zhounan insilicoscreeningidentifiesanovelpotentialparp1inhibitortargetingsyntheticlethalityincancertreatment
AT caipeiling insilicoscreeningidentifiesanovelpotentialparp1inhibitortargetingsyntheticlethalityincancertreatment
AT baojinku insilicoscreeningidentifiesanovelpotentialparp1inhibitortargetingsyntheticlethalityincancertreatment