Identification of potential small molecule allosteric modulator sites on IL-1R1 ectodomain using accelerated...

Area of Science:

• Immunology
• Computational Biology
• Drug Discovery

Background:

• The interleukin-1 receptor (IL-1R) family plays a crucial role in innate immunity.
• Dysregulated cytokine production contributes to autoimmune and inflammatory diseases.
• Current therapies for IL-1R-mediated diseases often involve biologics, with challenges in developing small molecule inhibitors due to large protein-protein interfaces.

Purpose of the Study:

• To explore the hypothesis that transient small molecule binding sites exist on the IL-1R type 1 (IL-1R1) ectodomain during conformational transitions.
• To identify potential allosteric modulator sites for small molecule inhibitor development targeting IL-1R.

Main Methods:

• Accelerated molecular dynamics (MD) simulations were used to sample the conformational space of the IL-1R1 ectodomain.
• Hierarchy cluster analysis identified representative conformations, which were then analyzed using the SiteMap program to locate potential binding sites.
• Cosolvent mapping with phenol confirmed an allosteric modulator site as a binding hotspot, and in silico screening identified fragment molecules for further MD evaluation.

Main Results:

• Small molecule binding sites were identified at the protein-protein interaction interface and at allosteric modulator locations.
• Cosolvent mapping validated the allosteric modulator site as a key binding hotspot.
• MD simulations of four top-ranked fragment molecules showed they could restrict IL-1R1 dynamics to inactive conformations.

Conclusions:

• The study presents a strategy for identifying small molecule inhibitors targeting allosteric sites on IL-1R.
• This approach, by trapping IL-1R in inactive conformations, could prevent cytokine binding and offer a novel therapeutic avenue for inflammatory conditions.
• Further in vitro experimental validation is required to confirm the efficacy of this strategy.