Identification of potential interleukin-8 inhibitors acting on the interactive site between chemokine and CXCR2
Thi-Thuy-Nga Tran1,2, Que-Huong Tran1,2, Quoc-Thai Nguyen1
1Faculty of Pharmacy, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam.
Abstract:
Interactions between interleukin (IL)-8 and its receptors, CXCR1, and CXCR2, serve crucial roles in inflammatory conditions and various types of cancers. Inhibition of this signaling pathway has been exploited as a promising strategy in treating these diseases. However, most studies only focused on the design of allosteric antagonists-bound receptors on the intracellular side of IL-8 receptors. Recently, the first cryo-EM structures of IL-8-CXCR2-Gi complexes have been solved, revealing the unique binding and activation modes of the endogenous chemokine IL-8. Hence, we set to identify small molecule inhibitors for IL-8 using critical protein-protein interaction between IL-8 and CXCR2 at the orthosteric binding site. The pharmacophore models and molecular docking screened compounds from DrugBank and NCI databases. The oral bioavailability of the top 23 ligands from the screening was then predicted by the SwissAMDE tool. Molecular dynamics simulation and free binding energy calculation were performed for the best compounds. The result indicated that DB14770, DB12121, and DB03916 could form strong interactions and stable protein-ligand complexes with IL-8. These three candidates are potential IL-8 inhibitors that can be further evaluated by in vitro experiments in the next stage.
Insights
Researchers identified novel small molecule inhibitors targeting the interleukin-8 (IL-8) and CXCR2 interaction. These compounds show potential for treating inflammatory diseases and cancers by blocking this critical signaling pathway.
Area of Science:
- Biochemistry
- Pharmacology
- Structural Biology
Background:
- Interleukin-8 (IL-8) and its receptors (CXCR1, CXCR2) are key players in inflammation and cancer.
- Targeting the IL-8 signaling pathway is a promising therapeutic strategy.
- Previous research focused on allosteric antagonists; orthosteric inhibition offers a new approach.
Purpose of the Study:
- To identify small molecule inhibitors targeting the orthosteric binding site of the IL-8/CXCR2 interaction.
- To discover novel therapeutic agents for inflammatory conditions and cancers.
Main Methods:
- Pharmacophore modeling and molecular docking were used to screen DrugBank and NCI databases.
- Oral bioavailability was predicted using the SwissAMDE tool.
- Molecular dynamics simulations and binding energy calculations were performed for top candidates.
Main Results:
- Twenty-three potential ligands were identified.
- DB14770, DB12121, and DB03916 demonstrated strong interactions and stable complexes with IL-8.
- These compounds represent promising candidates for IL-8 inhibition.
Conclusions:
- DB14770, DB12121, and DB03916 are identified as potential IL-8 inhibitors.
- These candidates warrant further in vitro evaluation for therapeutic potential.
- Targeting the IL-8/CXCR2 orthosteric site is a viable strategy for drug discovery.
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