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Discovery of novel anti-tumor compounds targeting PARP-1 with induction of autophagy through in silico and in vitro screening

Poly (ADP-ribose) polymerase 1 (PARP-1) is a critical enzyme involved in DNA damage repair and recombination, and shows great potential for drug development in the treatment of cancers with defective DNA repair. The anti-tumor activities of PARP-1 inhibitors are regulated by both inhibition activiti...

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Autores principales: Shi, Danfeng, Pang, Qianqian, Qin, Qianyu, Yao, Xinsheng, Yao, Xiaojun, Yu, Yang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9638114/
https://www.ncbi.nlm.nih.gov/pubmed/36353483
http://dx.doi.org/10.3389/fphar.2022.1026306
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author Shi, Danfeng
Pang, Qianqian
Qin, Qianyu
Yao, Xinsheng
Yao, Xiaojun
Yu, Yang
author_facet Shi, Danfeng
Pang, Qianqian
Qin, Qianyu
Yao, Xinsheng
Yao, Xiaojun
Yu, Yang
author_sort Shi, Danfeng
collection PubMed
description Poly (ADP-ribose) polymerase 1 (PARP-1) is a critical enzyme involved in DNA damage repair and recombination, and shows great potential for drug development in the treatment of cancers with defective DNA repair. The anti-tumor activities of PARP-1 inhibitors are regulated by both inhibition activities and allosteric mechanisms of PARP-1, and may also be involved in an autophagy-mediated process. Screening PARP-1 inhibitors with potential allosteric mechanisms and induced autophagy process could achieve elevated potency toward cancer cell killing. In this study, we tried to discover novel anti-tumor compounds targeting PARP-1 by computer simulations and in vitro screening. In order to filter PARP-1 inhibitors that could affect the folding state of the helix domain (HD) on PARP-1, the free energy contribution of key residues on HD were systematically analyzed using the ligand-binding crystal structures and integrated into in silico screening workflow for the selection of 20 pick-up compounds. Four compounds (Chemdiv codes: 8012-0567, 8018-6529, 8018-7168, 8018-7603) were proved with above 40% inhibitory ratio targeting PARP-1 under 20 μM, and further performed binding mode prediction and dynamic effect evaluation by molecular dynamics simulation. Further in vitro assays showed that compounds 8018-6529 and 8018-7168 could inhibit the growth of the human colorectal cancer cell (HCT-116) with IC50 values of 4.30 and 9.29 μM and were accompanied with an induced autophagy process. Taken together, we discover two novel anti-tumor compounds that target PARP-1 with an induced autophagy process and provide potential hit compounds for the anti-cancer drug development.
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spelling pubmed-96381142022-11-08 Discovery of novel anti-tumor compounds targeting PARP-1 with induction of autophagy through in silico and in vitro screening Shi, Danfeng Pang, Qianqian Qin, Qianyu Yao, Xinsheng Yao, Xiaojun Yu, Yang Front Pharmacol Pharmacology Poly (ADP-ribose) polymerase 1 (PARP-1) is a critical enzyme involved in DNA damage repair and recombination, and shows great potential for drug development in the treatment of cancers with defective DNA repair. The anti-tumor activities of PARP-1 inhibitors are regulated by both inhibition activities and allosteric mechanisms of PARP-1, and may also be involved in an autophagy-mediated process. Screening PARP-1 inhibitors with potential allosteric mechanisms and induced autophagy process could achieve elevated potency toward cancer cell killing. In this study, we tried to discover novel anti-tumor compounds targeting PARP-1 by computer simulations and in vitro screening. In order to filter PARP-1 inhibitors that could affect the folding state of the helix domain (HD) on PARP-1, the free energy contribution of key residues on HD were systematically analyzed using the ligand-binding crystal structures and integrated into in silico screening workflow for the selection of 20 pick-up compounds. Four compounds (Chemdiv codes: 8012-0567, 8018-6529, 8018-7168, 8018-7603) were proved with above 40% inhibitory ratio targeting PARP-1 under 20 μM, and further performed binding mode prediction and dynamic effect evaluation by molecular dynamics simulation. Further in vitro assays showed that compounds 8018-6529 and 8018-7168 could inhibit the growth of the human colorectal cancer cell (HCT-116) with IC50 values of 4.30 and 9.29 μM and were accompanied with an induced autophagy process. Taken together, we discover two novel anti-tumor compounds that target PARP-1 with an induced autophagy process and provide potential hit compounds for the anti-cancer drug development. Frontiers Media S.A. 2022-10-24 /pmc/articles/PMC9638114/ /pubmed/36353483 http://dx.doi.org/10.3389/fphar.2022.1026306 Text en Copyright © 2022 Shi, Pang, Qin, Yao, Yao and Yu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Shi, Danfeng
Pang, Qianqian
Qin, Qianyu
Yao, Xinsheng
Yao, Xiaojun
Yu, Yang
Discovery of novel anti-tumor compounds targeting PARP-1 with induction of autophagy through in silico and in vitro screening
title Discovery of novel anti-tumor compounds targeting PARP-1 with induction of autophagy through in silico and in vitro screening
title_full Discovery of novel anti-tumor compounds targeting PARP-1 with induction of autophagy through in silico and in vitro screening
title_fullStr Discovery of novel anti-tumor compounds targeting PARP-1 with induction of autophagy through in silico and in vitro screening
title_full_unstemmed Discovery of novel anti-tumor compounds targeting PARP-1 with induction of autophagy through in silico and in vitro screening
title_short Discovery of novel anti-tumor compounds targeting PARP-1 with induction of autophagy through in silico and in vitro screening
title_sort discovery of novel anti-tumor compounds targeting parp-1 with induction of autophagy through in silico and in vitro screening
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9638114/
https://www.ncbi.nlm.nih.gov/pubmed/36353483
http://dx.doi.org/10.3389/fphar.2022.1026306
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