Large-scale comparative virtual screening identifies novel molecular targets underlying the multi-target activity of...

Psoriasis is a chronic inflammatory skin disorder arising from immune dysregulation, cytokine storms, and excessive keratinocyte proliferation. Because single-target therapies often show limited efficacy, drug resistance, high costs, and long-term safety concerns, we performed the first large-scale comparative virtual screening of 32 dietary flavonoids against 20 psoriasis-related protein targets to identify safe and cost-effective multi-target therapeutic candidates. Consensus docking predicted quercetin as the top hit, exhibiting a broad binding profile across 11 targets, including previously reported ones (PI3Kδ, the JAK family, PDE4D, and p38α-MAPK) and four newly predicted putative targets (BTK, RORγt, CTSS, and PKCθ). Duplicate molecular dynamics simulations with principal component analysis, free energy landscape, and clustering analyses further characterized these interactions. RORγt and PI3Kδ exhibited the most favourable binding characteristics, followed by the JAK family, whereas PDE4D and PKCθ showed comparatively weaker yet promising interactions. Although quercetin has previously been associated with psoriasis through its antioxidant and immunomodulatory properties, its direct molecular targets and binding mechanisms have remained largely unresolved. Here, quercetin consistently outperformed the other 31 flavonoids while maintaining relative target selectivity. The predicted interaction of quercetin with RORγt provided computational structural support for modulation of the IL-23/IL-17 axis and helped explain quercetin effects on Th17-cell differentiation. Similarly, computationally predicted interactions provided a structural rationale for several other well-documented yet mechanistically unresolved anti-inflammatory and immunomodulatory effects of quercetin, indicating that its therapeutic activity may extend across multiple disease-relevant cell types and signalling pathways. Furthermore, this study presents the atomic-level structural characterization of quercetin binding to newly predicted putative targets and previously known targets lacking complex structural data. Collectively, these findings expand the molecular understanding of quercetin in psoriasis, provide a computational framework for multi-target drug discovery, and highlight the need for experimental validation and enhancement of bioavailability as essential next steps toward clinical translation.