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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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.1026306/full |
| _version_ | 1798030816577585152 |
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| author | Danfeng Shi Qianqian Pang Qianyu Qin Xinsheng Yao Xiaojun Yao Yang Yu |
| author_facet | Danfeng Shi Qianqian Pang Qianyu Qin Xinsheng Yao Xiaojun Yao Yang Yu |
| author_sort | Danfeng Shi |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-11T19:46:22Z |
| format | Article |
| id | doaj.art-caec762116834123a9e607f49307c0d9 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-11T19:46:22Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-caec762116834123a9e607f49307c0d92022-12-22T04:06:27ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-10-011310.3389/fphar.2022.10263061026306Discovery of novel anti-tumor compounds targeting PARP-1 with induction of autophagy through in silico and in vitro screeningDanfeng Shi0Qianqian Pang1Qianyu Qin2Xinsheng Yao3Xiaojun Yao4Yang Yu5Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou, ChinaGuangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou, ChinaGuangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou, ChinaGuangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, ChinaGuangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou, ChinaPoly (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.https://www.frontiersin.org/articles/10.3389/fphar.2022.1026306/fullPARP-1 inhibitoranti-tumorin silico screeningautophagyallosteric |
| spellingShingle | Danfeng Shi Qianqian Pang Qianyu Qin Xinsheng Yao Xiaojun Yao Yang Yu Discovery of novel anti-tumor compounds targeting PARP-1 with induction of autophagy through in silico and in vitro screening Frontiers in Pharmacology PARP-1 inhibitor anti-tumor in silico screening autophagy allosteric |
| 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 | PARP-1 inhibitor anti-tumor in silico screening autophagy allosteric |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.1026306/full |
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