ArticlePloS one2015
Identification of potential small molecule allosteric modulator sites on IL-1R1 ectodomain using accelerated conformational sampling method.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 43 citations in OpenAlex.
- Antagonist Binding Actively Disrupts Interleukin-1 Receptor Dynamics to Block Co-receptor Recruitment.Computational and structural biotechnology journal · 2026Article
- Evaluation of Small-Molecule Binding Site Prediction Methods on Membrane-Embedded Protein Interfaces.Journal of chemical information and modeling · 2025Article
- Structural and dynamic properties of IL1 receptors.Frontiers in immunology · 2025Review
- Out of Box Thinking to Tangible Science: A Benchmark History of 3D Bio-Printing in Regenerative Medicine and Tissues Engineering.Life (Basel, Switzerland) · 2023Review
- Article
- Optimization of IL-1RA structure to achieve a smaller protein with a higher affinity to its receptor.Scientific reports · 2022Article
- Computational Cosolvent Mapping Analysis Leads to Identify Salicylic Acid Analogs as Weak Inhibitors of ST2 and IL33 Binding.The journal of physical chemistry. B · 2022Article
- Membrane Hormone Receptors and Their Signaling Pathways as Targets for Endocrine Disruptors.Journal of xenobiotics · 2022Review
- Conformational Dynamics of the Soluble and Membrane-Bound Forms of Interleukin-1 Receptor Type-1: Insights into Linker Flexibility and Domain Orientation.International journal of molecular sciences · 2022Article
- The Therapeutic Prospects of Targeting IL-1R1 for the Modulation of Neuroinflammation in Central Nervous System Disorders.International journal of molecular sciences · 2022Review
- Application of Site-Identification by Ligand Competitive Saturation in Computer-Aided Drug Design.New journal of chemistry = Nouveau journal de chimie · 2022Article
- Molecular Dynamics Simulation Techniques as Tools in Drug Discovery and Pharmacology: A Focus on Allosteric Drugs.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Interleukin-36: Structure, Signaling and Function.Advances in experimental medicine and biology · 2021Review
- Big data and artificial intelligence discover novel drugs targeting proteins without 3D structure and overcome the undruggable targets.Stroke and vascular neurology · 2020Review
- Structure-based discovery of CZL80, a caspase-1 inhibitor with therapeutic potential for febrile seizures and later enhanced epileptogenic susceptibility.British journal of pharmacology · 2020Article
- Comparative Analyses of the Conformational Dynamics Between the Soluble and Membrane-Bound Cytokine Receptors.Scientific reports · 2020Article
- Small Molecule IL-36γ Antagonist as a Novel Therapeutic Approach for Plaque Psoriasis.Scientific reports · 2019Article
- Structural Basis of IL-1 Family Cytokine Signaling.Frontiers in immunology · 2019Review
- Article
- In silico structure-based approaches to discover protein-protein interaction-targeting drugs.Methods (San Diego, Calif.) · 2017Review
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Authors and funding
1 author at 1 institution in 1 country.
Funding
Abstract
The interleukin-1 receptor (IL-1R) is the founding member of the interleukin 1 receptor family which activates innate immune response by its binding to cytokines. Reports showed dysregulation of cytokine production leads to aberrant immune cells activation which contributes to auto-inflammatory disorders and diseases. Current therapeutic strategies focus on utilizing antibodies or chimeric cytokine biologics. The large protein-protein interaction interface between cytokine receptor and cytokine poses a challenge in identifying binding sites for small molecule inhibitor development. Based on the significant conformational change of IL-1R type 1 (IL-1R1) ectodomain upon binding to different ligands observed in crystal structures, we hypothesized that transient small molecule binding sites may exist when IL-1R1 undergoes conformational transition and thus suitable for inhibitor development. Here, we employed accelerated molecular dynamics (MD) simulation to efficiently sample conformational space of IL-1R1 ectodomain. Representative IL-1R1 ectodomain conformations determined from the hierarchy cluster analysis were analyzed by the SiteMap program which leads to identify small molecule binding sites at the protein-protein interaction interface and allosteric modulator locations. The cosolvent mapping analysis using phenol as the probe molecule further confirms the allosteric modulator site as a binding hotspot. Eight highest ranked fragment molecules identified from in silico screening at the modulator site were evaluated by MD simulations. Four of them restricted the IL-1R1 dynamical motion to inactive conformational space. The strategy from this study, subject to in vitro experimental validation, can be useful to identify small molecule compounds targeting the allosteric modulator sites of IL-1R and prevent IL-1R from binding to cytokine by trapping IL-1R in inactive conformations.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.