Identification of Novel Covalent XPO1 Inhibitors Based on a Hybrid Virtual Screening Strategy
Zheyuan Shen1,2, Weihao Zhuang3, Kang Li4
1Department of Urology, Rui'an People's Hospital, the Third Affiliated Hospital of Wenzhou Medical University, Wenzhou 325200, China.
Abstract:
Nuclear export protein 1 (XPO1), a member of the nuclear export protein-p (Karyopherin-P) superfamily, regulates the transport of "cargo" proteins. To facilitate this important process, which is essential for cellular homeostasis, XPO1 must first recognize and bind the cargo proteins. To inhibit this process, small molecule inhibitors have been designed that inhibit XPO1 activity through covalent binding. However, the scaffolds for these inhibitors are very limited. While virtual screening may be used to expand the diversity of the XPO1 inhibitor skeleton, enormous computational resources would be required to accomplish this using traditional screening methods. In the present study, we report the development of a hybrid virtual screening workflow and its application in XPO1 covalent inhibitor screening. After screening, several promising XPO1 covalent molecules were obtained. Of these, compound 8 performed well in both tumor cell proliferation assays and a nuclear export inhibition assay. In addition, molecular dynamics simulations were performed to provide information on the mode of interaction of compound 8 with XPO1. This research has identified a promising new scaffold for XPO1 inhibitors, and it demonstrates an effective and resource-saving workflow for identifying new covalent inhibitors.
Insights
Researchers developed a novel hybrid virtual screening workflow to identify new XPO1 covalent inhibitors. This efficient method discovered promising drug candidates, including compound 8, which effectively inhibits tumor cell proliferation and nuclear export.
Area of Science:
- Molecular Biology
- Drug Discovery
- Computational Chemistry
Background:
- Nuclear export protein 1 (XPO1) is crucial for cellular homeostasis, regulating protein transport.
- XPO1 inhibitors are limited in scaffold diversity, hindering drug development.
- Traditional virtual screening for XPO1 inhibitors demands extensive computational resources.
Purpose of the Study:
- To develop an efficient, resource-saving hybrid virtual screening workflow for XPO1 covalent inhibitors.
- To identify novel molecular scaffolds for XPO1 covalent inhibitors.
- To evaluate the efficacy of identified compounds in inhibiting XPO1 activity and tumor cell proliferation.
Main Methods:
- Development and application of a hybrid virtual screening workflow.
- Screening of potential XPO1 covalent inhibitor molecules.
- In vitro assays including tumor cell proliferation and nuclear export inhibition.
- Molecular dynamics simulations to elucidate compound-XPO1 interactions.
Main Results:
- Identification of several promising XPO1 covalent inhibitor candidates.
- Compound 8 demonstrated significant efficacy in tumor cell proliferation and nuclear export inhibition assays.
- Molecular dynamics simulations provided insights into the binding mode of compound 8 with XPO1.
Conclusions:
- The study identified a novel and promising scaffold for XPO1 inhibitors.
- The developed hybrid virtual screening workflow is effective and resource-efficient for discovering covalent inhibitors.
- Compound 8 represents a potential therapeutic lead for further investigation.
