1. Targeting ATP-binding site of WRN Helicase: Identification of novel inhibitors through pocket analysis and Molecular Dynamics-Enhanced virtual screening.
- Author
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Yuan H, Liu RD, Gao ZY, Zhong LT, Zhou YC, Tan JH, Huang ZS, Li Z, and Chen SB
- Subjects
- Binding Sites, Drug Screening Assays, Antitumor, Microsatellite Instability drug effects, Neoplasms genetics, Humans, Adenosine Triphosphate chemistry, Molecular Dynamics Simulation, Werner Syndrome Helicase antagonists & inhibitors, Werner Syndrome Helicase chemistry, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology
- Abstract
WRN helicase is a critical protein involved in maintaining genomic stability, utilizing ATP hydrolysis to dissolve DNA secondary structures. It has been identified as a promising synthetic lethal target for microsatellite instable (MSI) cancers. However, few WRN helicase inhibitors have been discovered, and their potential binding sites remain unexplored. In this study, we analyzed potential binding sites for WRN inhibitors and focused on the ATP-binding site for screening new inhibitors. Through molecular dynamics-enhanced virtual screening, we identified two compounds, h6 and h15, which effectively inhibited WRN's helicase and ATPase activity in vitro. Importantly, these compounds selectively targeted WRN's ATPase activity, setting them apart from other non-homologous proteins with ATPase activity. In comparison to the homologous protein BLM, h6 exhibits some degree of selectivity towards WRN. We also investigated the binding mode of these compounds to WRN's ATP-binding sites. These findings offer a promising strategy for discovering new WRN inhibitors and present two novel scaffolds, which might be potential for the development of MSI cancer treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)
- Published
- 2024
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