The final, formatted version of the article will be published soon.
ORIGINAL RESEARCH article
Front. Chem.
Sec. Medicinal and Pharmaceutical Chemistry
Volume 12 - 2024 |
doi: 10.3389/fchem.2024.1451574
Structure-Based Virtual Screening towards the Discovery of Novel thrombin Inhibitors with Anti-HCC Activities
Provisionally accepted- 1 Department of Mental Health, Changzhi Medical College, Changzhi, Shanxi, 046000, China, Changzhi, China
- 2 Department of Chemistry, Changzhi University, Changzhi, China
Hepatic carcinoma (HCC) is one of the most lethal malignant tumors in the world, and new treatment regimens for this disease are urgently needed. Studies have shown that thrombin stimulates tumor progression by forming fibrin and activating platelets. Dabigatran etexilate, a thrombin inhibitor, can inhibit the activity of thrombin and prevent the proliferation and metastasis of HCC in cells and nude mice. The present study was designed to find thrombin inhibitors with novel skeletons, and further confirm the correlation between thrombin inhibition and HCC prevention to identify potential anti-HCC drug leads. The potential thrombin inhibitors were firstly screened in the Topscience Database, and 20 potential active molecules were found by molecular docking. The effect of these molecules on thrombin inhibition, coagulation and tumor proliferation were evaluated, and the definite activity of ZXX-4 was identified. Further in vivo assays in nude mice showed that ZXX-4 inhibited tumor proliferation in nude mice, reduced tumor metastasis, and enhanced the clinical efficacy of first-line drug sorafenib for the treatment of HCC. ZXX-4 can be further explored as an anti-tumor lead compound with a novel skeleton, and inhibition of thrombin can serve as a potential treatment strategy for HCC.Introduction
Keywords: Thrombin, Hepatic carcinoma, Computer-assisted drug design, molecular docking, In vitro experiment
Received: 19 Jun 2024; Accepted: 02 Sep 2024.
Copyright: © 2024 Zhang, Zheng, Han and Wu. 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:
Lintao Wu, Department of Chemistry, Changzhi University, Changzhi, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.