AI Article Synopsis
- Microsatellite instability (MSI) is linked to various cancers, and Werner syndrome ATP-dependent helicase (WRN) is a promising treatment target, particularly for colorectal cancer with high MSI levels.
- The study utilized computer-assisted drug discovery methods to screen over 30,000 natural products, identifying several potential WRN inhibitors based on docking and binding efficiency calculations.
- Molecular dynamics simulations showed these natural products bind more effectively than ATP and could inhibit the WRN dynamic process, highlighting their potential as competitive inhibitors for cancer treatment.
Article Abstract
Microsatellite instability (MSI) is a relatively common feature associated with multiple cancers, and Werner syndrome (WRN) ATP-dependent helicase has been recognized as a novel target for treating MSI cancers, such as colorectal cancer. A small-molecule inhibitor targeting WRN would be a promising strategy for treating colorectal cancer with high MSI expression. In this study, we employed a computer-assisted drug discovery strategy to screen over 30,000 natural product molecules. By using a combination of docking, ligand efficiency, Molecular Mechanics/Generalized Born Surface Area (MM/GBSA), and thermodynamic integration (TI) calculations, we identified MOL008980, MOL010740, MOL011832, T4743, TN1166, and TNP-002173 as potential WRN inhibitors. Subsequent molecular dynamics simulation revealed that these screened natural products possessed better binding dynamic characteristics than ATP substrate and were capable of inhibiting the dynamic process of WRN, making them potential strong ATP competitive inhibitors. In conclusion, our computational approach revealed potential WRN inhibitors from a natural product database, providing a theoretical basis for future research.
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| http://dx.doi.org/10.1016/j.jmgm.2024.108758 | DOI Listing |
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Article Synopsis
- Some cancer cells that have a condition called microsatellite instability (MSI) can't survive without a protein called WRN, while others without this condition (called microsatellite-stable or MSS) can.
- Scientists are exploring new ways to create drugs that can target WRN for these MSI cancer cells because normal WRN inhibitors might not work well against them.
- They designed a special tool called PROTAC that helps chop up WRN specifically in MSI cancer cells, which made those cells very sick, showing this method might be a great way to treat MSI cancers in the future.
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