Dataset Information

Effective natural inhibitors targeting poly ADP-ribose polymerase by computational study.

ABSTRACT:

Object

This study was designed to screen ideal lead compounds and drug candidates with an inhibitory effect on PARP from the drug library (ZINC database).

Results

Two effective natural compounds ZINC000003938684 and ZINC000014811844 were found to bind to PARP in the ZINC database, showing a higher binding affinity. Also, they were predicted to have lower rodent carcinogenicity, Ames mutagenicity, developmental toxicity potential, and high tolerance to cytochrome P4502D6. Molecular dynamics simulation showed that ZINC000003938684 and ZINC000014811844 had a more favorable potential energies with PARP, which could exist stably in natural circumstances.

Conclusion

This study suggested that ZINC000003938684 and ZINC000014811844 were ideal potential inhibitors of PARP targeting. These compounds were safe drug candidates and had important implications for the design and improvement of CMET target drugs.

Methods

A battery of computer-aided virtual techniques were used to identify potential inhibitors of PARP. LibDock is used for structure-based screening followed by ADME (absorption distribution, metabolic excretion) and toxicity prediction. Molecular docking was performed to demonstrate the binding affinity mechanism between the ligand and PARP. Molecular dynamics simulations were used to evaluate the stability of ligand-receptor complexes.

SUBMITTER: Zhong S

PROVIDER: S-EPMC7880371 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Effective natural inhibitors targeting poly ADP-ribose polymerase by computational study.

Zhong Sheng S Wu Bo B Yang Wenzhuo W Ge Junliang J Zhang Xiangheng X Chen Zhenghe Z Duan Hao H He Zhenqiang Z Liu Yibing Y Wang Hongyu H Jiang Yuting Y Zhang Zhiyun Z Wang Xinhui X Li Weihang W Liu Naimeng N Guo Xiaoyu X Mou Yonggao Y

Aging 20210123 2

<h4>Object</h4>This study was designed to screen ideal lead compounds and drug candidates with an inhibitory effect on PARP from the drug library (ZINC database).<h4>Results</h4>Two effective natural compounds ZINC000003938684 and ZINC000014811844 were found to bind to PARP in the ZINC database, showing a higher binding affinity. Also, they were predicted to have lower rodent carcinogenicity, Ames mutagenicity, developmental toxicity potential, and high tolerance to cytochrome P4502D6. Molecular ...[more]

PMID: 33486472

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Project description:Poly(ADP-ribose) polymerases (PARPs) are involved in many aspects of the cellular response to various forms of damage. PARP-1 and PARP-2, the most abundant PARPs, are central to the response to specific types of DNA damage, especially single-strand breaks. Inhibition of PARP activity may sensitize the cell to exogenous agents such as chemotherapy and radiation. In circumstances where rescue pathways are deficient, particularly the homologous recombination (HR)-directed DNA repair pathway, inhibition of PARP may result in "synthetic lethality." BRCA mutation-associated breast cancers are a paradigm of HR-directed repair deficient tumors. Early clinical trials have demonstrated significant activity of single-agent PARP inhibitors in BRCA-deficient breast and ovarian cancer. Because of phenotypic similarities between some "triple-negative" breast cancers (TNBC) and the most prevalent type of breast cancer seen in BRCA1 mutation carriers, some have hypothesized that TNBC might also be specifically sensitive to PARP inhibition. The activity of single-agent PARP inhibitors in TNBC has not been reported. One trial did suggest significant enhancement of the activity of platinum-based combination chemotherapy, without incremental toxicity. These studies indicate that PARP inhibition is an exciting new approach to the treatment of breast cancers in women with underlying BRCA mutations and possibly in sporadic cancers with defects in HR-directed repair. Future studies will be necessary to determine whether the effectiveness of PARP inhibitors in nonhereditary cancer requires an underlying HR defect or whether these agents may improve the activity of conventional chemotherapy by other means. In addition, studies will be required to determine whether PARP inhibitors may induce synthetic lethality in tumors with defects in pathways other than the BRCA-dependent DNA repair pathway. If either or both of these prove to be the case, then PARP inhibition may benefit a wide spectrum of cancer patients.

Dataset Information

Effective natural inhibitors targeting poly ADP-ribose polymerase by computational study.

Object

Results

Conclusion

Methods

Publications

Effective natural inhibitors targeting poly ADP-ribose polymerase by computational study.

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