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<p>Dysregulated Janus kinase–signal transducer and activator of transcription (JAK-STAT) signalling is a hallmark of psoriasis, a long-term, immune-mediated inflammatory skin condition. The preclinical pharmacological profile and structural binding mechanism of tofacitinib, a pan-JAK inhibitor, in the Imiquimod (IMQ)-induced mouse model are still not well understood, despite its therapeutic effectiveness in psoriasis. Using molecular docking and 200 ns molecular dynamics (MD) simulation, assess tofacitinib’s in vivo anti-psoriatic effectiveness in the IMQ-induced BALB/c mouse model and describe its binding interactions with the JAK2 kinase domain (PDB: 3FUP). Topical IMQ (62.5&#xa0;mg/day) was administered to BALB/c mice for seven days. Dexamethasone (1&#xa0;mg/kg, p.o.) and tofacitinib (1, 3, 10&#xa0;mg/kg, p.o., b.i.d.) were given at the same time. Psoriasis Area and Severity Index (PASI) scores, body weight, ear thickness, cytokine levels (IL-1β, IL-6, IL-17&#xa0;A, and IL-10; RT-PCR and ELISA), and histopathological characteristics were evaluated. Glide XP (Schrödinger) was used for molecular docking, while Desmond (Schrödinger) was used for MD simulation utilising the OPLS4 force field over 200 ns. Tofacitinib (3 and 10&#xa0;mg/kg) was equally effective as dexamethasone in reducing ear thickness, PASI scores, and pro-inflammatory cytokines (IL-1β, IL-6, and IL-17&#xa0;A) while also improving histopathological markers and restoring IL-10 levels. Molecular docking demonstrated that tofacitinib has a higher binding affinity than dexamethasone (− 6.043&#xa0;kcal/mol; − 51.81&#xa0;kcal/mol), with crucial hydrogen bonds to LEU932 and GLU930 in the JAK2 hinge region (GlideScore: − 10.292&#xa0;kcal/mol; ΔG: − 96.20&#xa0;kcal/mol). Over 200 ns, MD modelling verified steady complex formation (RMSD: 1.95 Å; RMSF: 1.13 Å; Rg: 3.71 Å; SASA: 44.27 Å<sup>2</sup>). By inhibiting the JAK-STAT system, tofacitinib has notable anti-psoriatic activity in the IMQ model, and in silico investigations corroborate its strong structural binding stability. These results provide credence to JAK inhibition as a mechanistically sound psoriasis treatment approach.</p> Graphical abstract <p></p>

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Tofacitinib attenuates imiquimod-induced psoriasis via JAK-STAT inhibition: in vivo and in silico study

  • 期刊论文

  • 发表日期：

    2026年6月22日

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  • Vinay Kumar,
  • Shardendu Kumar Mishra,
  • Ruqaiya Jamal,
  • Mohamad Taleuzzaman

摘要

Dysregulated Janus kinase–signal transducer and activator of transcription (JAK-STAT) signalling is a hallmark of psoriasis, a long-term, immune-mediated inflammatory skin condition. The preclinical pharmacological profile and structural binding mechanism of tofacitinib, a pan-JAK inhibitor, in the Imiquimod (IMQ)-induced mouse model are still not well understood, despite its therapeutic effectiveness in psoriasis. Using molecular docking and 200 ns molecular dynamics (MD) simulation, assess tofacitinib’s in vivo anti-psoriatic effectiveness in the IMQ-induced BALB/c mouse model and describe its binding interactions with the JAK2 kinase domain (PDB: 3FUP). Topical IMQ (62.5 mg/day) was administered to BALB/c mice for seven days. Dexamethasone (1 mg/kg, p.o.) and tofacitinib (1, 3, 10 mg/kg, p.o., b.i.d.) were given at the same time. Psoriasis Area and Severity Index (PASI) scores, body weight, ear thickness, cytokine levels (IL-1β, IL-6, IL-17 A, and IL-10; RT-PCR and ELISA), and histopathological characteristics were evaluated. Glide XP (Schrödinger) was used for molecular docking, while Desmond (Schrödinger) was used for MD simulation utilising the OPLS4 force field over 200 ns. Tofacitinib (3 and 10 mg/kg) was equally effective as dexamethasone in reducing ear thickness, PASI scores, and pro-inflammatory cytokines (IL-1β, IL-6, and IL-17 A) while also improving histopathological markers and restoring IL-10 levels. Molecular docking demonstrated that tofacitinib has a higher binding affinity than dexamethasone (− 6.043 kcal/mol; − 51.81 kcal/mol), with crucial hydrogen bonds to LEU932 and GLU930 in the JAK2 hinge region (GlideScore: − 10.292 kcal/mol; ΔG: − 96.20 kcal/mol). Over 200 ns, MD modelling verified steady complex formation (RMSD: 1.95 Å; RMSF: 1.13 Å; Rg: 3.71 Å; SASA: 44.27 Å2). By inhibiting the JAK-STAT system, tofacitinib has notable anti-psoriatic activity in the IMQ model, and in silico investigations corroborate its strong structural binding stability. These results provide credence to JAK inhibition as a mechanistically sound psoriasis treatment approach.

Graphical abstract