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

@article{Li2016InSS,
  title={In Silico Screening Identifies a Novel Potential PARP1 Inhibitor Targeting Synthetic Lethality in Cancer Treatment},
  author={Jian Li and Nan Zhou and Peiling Cai and Jinku Bao},
  journal={International Journal of Molecular Sciences},
  year={2016},
  volume={17}
}
  • Jian Li, N. Zhou, J. Bao
  • Published 1 February 2016
  • Biology, Chemistry
  • International Journal of Molecular Sciences
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… 

Figures and Tables from this paper

Identification of novel potential PI3Kα inhibitors for cancer therapy
TLDR
Significant insights are provided into the development and design of more potent PI3Kα-inhibiting analogs and it is demonstrated that TCM-N1 was tightly embedded into the ATP-binding pocket via hydrogen bonds, van der Waals interactions, and hydrophobic interactions.
Discovery of a Potential HER2 Inhibitor from Natural Products for the Treatment of HER2-Positive Breast Cancer
TLDR
Results reveal that ZINC15122021 can be a potential HER2 inhibitor and shows favorable ADMET properties and attained high binding affinity against HER2.
Systematic comparison of ligand-based and structure-based virtual screening methods on poly (ADP-ribose) polymerase-1 inhibitors
TLDR
These findings confirmed that adding ligand-based methods to the early screening stage will greatly improve the screening efficiency, and be able to enrich more highly active PARP1 inhibitors with diverse structures.
PARP1 in Carcinomas and PARP1 Inhibitors as Antineoplastic Drugs
TLDR
The structure, expression, functions, and mechanisms ofPARP1 are reviewed, the clinically mature PARP1-related anticancer agents are summarized, and some ideas for the development of other promising PARP 1 inhibitors in antineoplastic therapy are provided.
Compound F779-0434 causes synthetic lethality in BRCA2-deficient cancer cells by disrupting RAD52–ssDNA association
TLDR
A structure-based virtual screening of 47 737 drug-like compounds was performed to identify RAD52-specific inhibitors and it was found that one compound specifically suppressed the growth of BRCA2-deficient cells and disrupted RAD52–ssDNA interaction in vitro.
L1198F Mutation Resensitizes Crizotinib to ALK by Altering the Conformation of Inhibitor and ATP Binding Sites
TLDR
This study exploited molecular dynamics simulation to dissect the molecular mechanisms of the newest generation inhibitor resistant mutation of ALK and revealed that L1198F mutation resulted in the conformational change at the inhibitor site and altered the binding affinity of AlK to crizotinib and lorlatinib.
Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity
TLDR
Roles played by PARP enzymes in host-pathogen interactions and in diseases with an associated inflammatory response are focused on, and PARP inhibitors show promise in the treatment of inflammatory disorders and conditions with an inflammatory component.
Exploration of Binding Mechanism of a Potential Streptococcus pneumoniae Neuraminidase Inhibitor from Herbaceous Plants by Molecular Simulation
TLDR
The results predicted a detailed binding mechanism of a potential Streptococcus pneumoniae neuraminidase inhibitor, which will be provide a theoretical basis for the mechanism of new inhibitors.
...
...

References

SHOWING 1-10 OF 35 REFERENCES
A high-throughput screen identifies PARP1/2 inhibitors as a potential therapy for ERCC1-deficient non-small cell lung cancer
TLDR
It is suggested that PARP1/2 inhibitors as a monotherapy could represent a novel therapeutic strategy for NSCLC patients with ERCC1-deficient tumours.
Discover natural compounds as potential phosphodiesterase-4B inhibitors via computational approaches
  • Jing Li, N. Zhou, J. Bao
  • Biology, Chemistry
    Journal of biomolecular structure & dynamics
  • 2016
TLDR
It is expected that this study will pave the way for the design of potent PDE4B-selective inhibitors of new drugs to treat a wide variety of diseases such as asthma, COPD, psoriasis, depression, etc.
ATM-depletion in breast cancer cells confers sensitivity to PARP inhibition
TLDR
It is indicated that ATM-depletion can sensitize breast cancer cells to PARP inhibition, suggesting a potential in the treatment of breast cancers low in ATM protein expression/activity, such as those arising in mutant ATM heterozygous carriers.
Therapeutic Potential of the Poly(ADP-ribose) Polymerase Inhibitor Rucaparib for the Treatment of Sporadic Human Ovarian Cancer
TLDR
Rucaparib potentiated chemotherapy independent of its activity as a single agent and may be a useful therapeutic strategy for a wider range of ovarian cancers bearing deficiencies in the homologous recombination pathway other than just BRCA1/2 mutations.
In Silico Discovery of Potential VEGFR-2 Inhibitors from Natural Derivatives for Anti-Angiogenesis Therapy
  • Jing Li, N. Zhou, J. Bao
  • Biology, Chemistry
    International journal of molecular sciences
  • 2014
TLDR
Findings in this study are able to provide valuable information on discovery of effective anti-angiogenesis therapy and suggest these three compounds could be candidate drugs against angiogenesis, with comparable VEGFR-2 binding affinity of axitinib.
Enhanced cytotoxicity of PARP inhibition in mantle cell lymphoma harbouring mutations in both ATM and p53
TLDR
It is shown that mantle cell lymphoma (MCL) cells deficient in both ATM and p53 are more sensitive to the PARP inhibitor olaparib than cells lacking ATM function alone, and the combination of ATM and PARP inhibitors may have utility in targeting p53‐deficient malignancies.
The Concept of Synthetic Lethality in the Context of Anticancer Therapy
TLDR
Synthetic lethality provides a conceptual framework for the development of cancer-specific cytotoxic agents and has not been exploited in the past because there were no robust methods for systematically identifying synthetic lethal genes.
Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase
TLDR
It is proposed that, in the absence of PARP1, spontaneous single-strand breaks collapse replication forks and trigger homologous recombination for repair and exploited in order to kill BRCA2-deficient tumours by PARP inhibition alone.
Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition.
TLDR
The results indicate that PARP inhibition might be a useful therapeutic strategy not only for the treatment of BRCA mutation-associated tumors but also for a wider range of tumors bearing a variety of deficiencies in the HR pathway or displaying properties of 'BRCAness.
...
...