Kai Deng , Qiongqiong Li , Lina Lu , Luting Wang , Zhiyong Cheng , Suyun Wang
{"title":"治疗多发性骨髓瘤的蛋白酶体和 PARP1 双靶点抑制剂:氟唑帕尼","authors":"Kai Deng , Qiongqiong Li , Lina Lu , Luting Wang , Zhiyong Cheng , Suyun Wang","doi":"10.1016/j.bbrep.2024.101781","DOIUrl":null,"url":null,"abstract":"<div><p>One of the current mainstream treatments for multiple myeloma (MM) is chemotherapy. However, due to the high clonal heterogeneity and genomic complexity of MM, single-target drugs have limited efficacy and are prone to drug resistance. Therefore, there is an urgent need to develop multi-target drugs against MM. We screened drugs that simultaneously inhibit poly(ADP-ribose) polymerase 1 (PARP1) and 20S proteasome through computer-aided drug discovery (CADD) techniques, and explored the binding mode and dynamic stability of selected inhibitor to proteasome through Molecular biology (MD) simulation method. Thus, the dual-target inhibition effect of fluzoparib was proposed for the first time, and the ability of dual-target inhibition and tumor killing was explored at the enzyme, cell and animal level, respectively. This provides a theoretical and experimental basis for exploring multi-target inhibitory drugs for cancers.</p></div>","PeriodicalId":8771,"journal":{"name":"Biochemistry and Biophysics Reports","volume":null,"pages":null},"PeriodicalIF":2.3000,"publicationDate":"2024-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2405580824001456/pdfft?md5=562814c153e82dbbac7c67767214688c&pid=1-s2.0-S2405580824001456-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Proteasome and PARP1 dual-target inhibitor for multiple myeloma: Fluzoparib\",\"authors\":\"Kai Deng , Qiongqiong Li , Lina Lu , Luting Wang , Zhiyong Cheng , Suyun Wang\",\"doi\":\"10.1016/j.bbrep.2024.101781\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>One of the current mainstream treatments for multiple myeloma (MM) is chemotherapy. However, due to the high clonal heterogeneity and genomic complexity of MM, single-target drugs have limited efficacy and are prone to drug resistance. Therefore, there is an urgent need to develop multi-target drugs against MM. We screened drugs that simultaneously inhibit poly(ADP-ribose) polymerase 1 (PARP1) and 20S proteasome through computer-aided drug discovery (CADD) techniques, and explored the binding mode and dynamic stability of selected inhibitor to proteasome through Molecular biology (MD) simulation method. Thus, the dual-target inhibition effect of fluzoparib was proposed for the first time, and the ability of dual-target inhibition and tumor killing was explored at the enzyme, cell and animal level, respectively. This provides a theoretical and experimental basis for exploring multi-target inhibitory drugs for cancers.</p></div>\",\"PeriodicalId\":8771,\"journal\":{\"name\":\"Biochemistry and Biophysics Reports\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.3000,\"publicationDate\":\"2024-07-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S2405580824001456/pdfft?md5=562814c153e82dbbac7c67767214688c&pid=1-s2.0-S2405580824001456-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biochemistry and Biophysics Reports\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2405580824001456\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochemistry and Biophysics Reports","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2405580824001456","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
化疗是目前治疗多发性骨髓瘤(MM)的主流疗法之一。然而,由于多发性骨髓瘤具有高度的克隆异质性和基因组复杂性,单靶点药物的疗效有限,而且容易产生耐药性。因此,开发针对 MM 的多靶点药物迫在眉睫。我们通过计算机辅助药物发现(CADD)技术筛选出同时抑制聚(ADP-核糖)聚合酶1(PARP1)和20S蛋白酶体的药物,并通过分子生物学(MD)模拟方法探讨了所选抑制剂与蛋白酶体的结合模式和动态稳定性。从而首次提出了氟唑帕尼的双靶点抑制作用,并分别从酶水平、细胞水平和动物水平探讨了氟唑帕尼的双靶点抑制和杀瘤能力。这为探索癌症多靶点抑制药物提供了理论和实验依据。
Proteasome and PARP1 dual-target inhibitor for multiple myeloma: Fluzoparib
One of the current mainstream treatments for multiple myeloma (MM) is chemotherapy. However, due to the high clonal heterogeneity and genomic complexity of MM, single-target drugs have limited efficacy and are prone to drug resistance. Therefore, there is an urgent need to develop multi-target drugs against MM. We screened drugs that simultaneously inhibit poly(ADP-ribose) polymerase 1 (PARP1) and 20S proteasome through computer-aided drug discovery (CADD) techniques, and explored the binding mode and dynamic stability of selected inhibitor to proteasome through Molecular biology (MD) simulation method. Thus, the dual-target inhibition effect of fluzoparib was proposed for the first time, and the ability of dual-target inhibition and tumor killing was explored at the enzyme, cell and animal level, respectively. This provides a theoretical and experimental basis for exploring multi-target inhibitory drugs for cancers.
期刊介绍:
Open access, online only, peer-reviewed international journal in the Life Sciences, established in 2014 Biochemistry and Biophysics Reports (BB Reports) publishes original research in all aspects of Biochemistry, Biophysics and related areas like Molecular and Cell Biology. BB Reports welcomes solid though more preliminary, descriptive and small scale results if they have the potential to stimulate and/or contribute to future research, leading to new insights or hypothesis. Primary criteria for acceptance is that the work is original, scientifically and technically sound and provides valuable knowledge to life sciences research. We strongly believe all results deserve to be published and documented for the advancement of science. BB Reports specifically appreciates receiving reports on: Negative results, Replication studies, Reanalysis of previous datasets.