Discovery of natural RORγt inhibitor using machine learning, virtual screening, and in vivo validation

ML ensemble models predicted potential RORγt inhibitors from an NP library; subsequent chemotaxonomic classification of top-ranked hits prioritized protoberberine alkaloids. Six protoberberine alkaloids, which are predicted to bind RORγt via docking studies, were selected for experimental validation. Among them, berberine (Ber) and coptisine (Cop) potently inhibited Th17 differentiation in vitro. Surface plasmon resonance analysis demonstrated that both Ber and Cop directly bind to RORγt, with Cop exhibiting a stronger affinity for RORγt than Ber. Moreover, Cop demonstrated therapeutic efficacy in a preclinical mouse model of psoriasis. These results validate an integrated workflow, combining ML, chemotaxonomy, and experimental testing in vitro and in vivo, for the efficient discovery of novel RORγt inhibitors.

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Publication Details

Journal
Journal of Advanced Research
Published
2025-09-01
DOI
https://doi.org/10.1016/j.jare.2025.09.004
Citations
1
Primary Topic
Cytokine Signaling Pathways and Interactions
Type
article
Field-Weighted Citation Impact
1.05
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Discovery of natural RORγt inhibitor using machine learning, virtual screening, and in vivo validation

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Discovery of natural RORγt inhibitor using machine learning, virtual screening, and in vivo validation

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article en
1 citations

Abstract

ML ensemble models predicted potential RORγt inhibitors from an NP library; subsequent chemotaxonomic classification of top-ranked hits prioritized protoberberine alkaloids. Six protoberberine alkaloids, which are predicted to bind RORγt via docking studies, were selected for experimental validation. Among them, berberine (Ber) and coptisine (Cop) potently inhibited Th17 differentiation in vitro. Surface plasmon resonance analysis demonstrated that both Ber and Cop directly bind to RORγt, with Cop exhibiting a stronger affinity for RORγt than Ber. Moreover, Cop demonstrated therapeutic efficacy in a preclinical mouse model of psoriasis. These results validate an integrated workflow, combining ML, chemotaxonomy, and experimental testing in vitro and in vivo, for the efficient discovery of novel RORγt inhibitors.

Journal of Advanced Research
Incheon National University (KR), Kangwon National University (KR), Wright State University (US), New Generation University College (ET), National University College (PR), HealthInsight (US), Ajou University (KR)
Openalex Percentile: Top 18%
Cytokine Signaling Pathways and Interactions
1.05
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