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ORIGINAL RESEARCH article

Front. Mol. Biosci.
Sec. Biological Modeling and Simulation
Volume 11 - 2024 | doi: 10.3389/fmolb.2024.1441550

Discovery of an 8-oxoguanine regulator PCBP1 inhibitor by virtual screening and its synergistic effects with ROS-modulating agents in pancreatic cancer

Provisionally accepted
Kexiong Qiao Kexiong Qiao 1Chengjie Xu Chengjie Xu 1Chaolei Zhang Chaolei Zhang 2Qianqian Wang Qianqian Wang 3Jun Jiang Jun Jiang 3Zongrong Chen Zongrong Chen 3Liangjing Zhou Liangjing Zhou 1Shengnan Jia Shengnan Jia 1*Liping Cao Liping Cao 1,4*
  • 1 Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China, Hangzhou, Jiangsu Province, China
  • 2 Department of Emergency Medicine, Sir Run Run Shaw Hospital, Hangzhou, Jiangsu Province, China
  • 3 Sir Run Run Shaw Hospital, School of Medicine, Graduate School, Zhejiang University, Hangzhou, Zhejiang, China
  • 4 Zhejiang Engineering Research Center of Cognitive Healthcare, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine,, Hangzhou, Jiangsu Province, China

The final, formatted version of the article will be published soon.

    Drugs that target reactive oxygen species (ROS) metabolism have progressed the treatment of pancreatic cancer treatment, yet their efficacy remains poor because of the adaptation of cancer cells to high concentration of ROS. Cells cope with ROS by recognizing 8-oxoguanine residues and processing severely oxidized RNA, which make it feasible to improve the efficacy of ROSmodulating drugs in pancreatic cancer by targeting 8-oxoguanine regulators. In this study, we identified poly(rC)-binding protein 1 (PCBP1) as a potential oncogene in pancreatic cancer. By applying high-throughput virtual screening, we identified Compound 102 and Compound 934 (silychristin) as potential PCBP1 inhibitors. Computational molecular dynamics simulations and virtual alanine mutagenesis verified the structure-activity correlation between PCBP1 and the two identified compounds. These two compounds interfere with the PCBP1-RNA interaction and impair the ability of PCBP1 to process RNA, leading to intracellular R loop accumulation. Compound 934 synergized with ROS agent hydrogen peroxide to strongly improve induced cell death in pancreatic cancer cells. Our results provide valuable insights into the development of drugs that target PCBP1 and identified promising synergistic agents for ROS-modulating drugs in pancreatic cancer.

    Keywords: poly(rC)-binding protein 1 (PCBP1), Virtual Screening, Molecular Dynamics Simulation, Silychristin, R-loop, pancreatic cancer 1

    Received: 31 May 2024; Accepted: 24 Jul 2024.

    Copyright: © 2024 Qiao, Xu, Zhang, Wang, Jiang, Chen, Zhou, Jia and Cao. 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) or licensor 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.

    * Correspondence:
    Shengnan Jia, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China, Hangzhou, Jiangsu Province, China
    Liping Cao, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China, Hangzhou, Jiangsu Province, China

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