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Discovery of Peripherally Restricted Cannabinoid Receptor 1 Antagonists for Psoriasis Therapy Using AI and CADD

  • 이주영 (아주대학교 일반대학원)

초록/요약

Psoriasis is a chronic inflammatory skin disorder characterized by excessive immune activation and epidermal hyperplasia. Current cytokine-targeting therapies offer symptomatic relief but fail to address the underlying immune dysregulation. Cannabinoid receptor 1 (CB1R) has emerged as a critical regulator of inflammation; however, existing CB1R antagonists elicit central nervous system (CNS)-related adverse effects due to poor peripheral selectivity, leading to market withdrawal. To overcome this limitation, we employed artificial intelligence (AI) and computer-aided drug design (CADD) pipeline to discover peripherally acting CB1R-modulating compounds. Initial virtual screening and functional assays identified four first-generation hits with measurable CB1R inhibition but limited therapeutic efficacy. A subsequent similarity-based expansion generated 29 analogs, among which S- 17 and S-28 emerged as promising candidates. At a dose of 20 mg/kg, both compounds significantly ameliorated imiquimod-induced psoriasis-like inflammation, reducing erythema, scaling, epidermal hyperplasia, keratinocyte proliferation, macrophage infiltration, and pro-inflammatory cytokine expression in vivo. In vitro studies showed that S-17 and S-28 do not modulate T-cell proliferation or Th17 differentiation but markedly suppress LPS-induced cytokine production in macrophages, indicating a macrophage- centered anti-inflammatory mechanism. Pharmacological profiling revealed weak functional inhibition of CB1R signaling and no detectable orthosteric radioligand binding, suggesting low-affinity or non-orthosteric modes of CB1R interaction. Collectively, this study demonstrates the utility of AI- and CADD-guided screening for identifying peripherally active anti-inflammatory compounds and highlights S-17 and S-28 as promising CB1R-modulating candidates with therapeutic potential in psoriasis

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목차

Ⅰ. INTRODUCTION 1

Ⅱ. EXPERIMENTAL 3
1. Materials. 3
2. Tango™ GPCR cell-based β-arrestin assay 4
3. Mice 5
4. Hypothermia test 5
5. Catalepsy test 6
6. Psoriasis-like mouse models 6
7. Histology and immunohistochemistry staining 7
8. Isolation and T cell differentiation of splenic naïve CD4⁺ T cell 8
9. T cell proliferation assay 9
10. Cell cytotoxicity assay 9
11. Flow cytometric analysis 10
12. Cell culture 10
13. Cell viability assay 11
14. Real-time quantitative PCR 11
15. β-arrestin recruitment assay (DiscoverX PathHunter Assay) 12
16. cAMP accumulation assay (DiscoverX HitHunter Assay) 12
17. Radioligand binding assay (CB1R Competitive Binding) 13
18. Statistical analysis 14
Ⅲ. RESULTS 16
1. AI-assisted virtual screening workflow for identification of CB1R-selective hit candidates via dual ranksum strategies 16
2. Functional screening of CB1R hit compounds and selectivity assessment using Tango assays 19
3. Evaluation of BBB permeability in CB1R hit compounds through behavioral assessment 25
4. Efficacy of CB1R hit compounds in the IMQ-induced psoriasis mouse model 29
5. Discovery of new A-10 analogs via similarity-based virtual screening 32
6. Functional screening of 29 A-10 analogs and selectivity assessment using Tango assays 36
7. Evaluation of BBB permeability in A-10 analogs through behavioral assessment 40
8. Efficacy of A-10 analogs in IMQ-induced psoriasis mouse model 44
9. Dose-escalated evaluation of S-17 and S-28 in an IMQ-induced psoriasis model 47
10. Assessment of T cell and macrophage responses to S-17 and S-28 50
11. Pharmacological characterization of S-17 and S-28 at the CB1 receptor 54

Ⅳ. DISCUSSION 58

Ⅴ. REFFRENCES 60

Ⅵ. ABSTRACT IN KOREAN (국문 초록) 63

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