Esculin as a Novel Inhibitor of CCR1: Insights into Its Potential Role in Modulating Immune Responses

Background: Chemokine receptor CCR1 plays a pivotal role in regulating immune responses, including leukocyte migration and inflammatory signaling pathways. Dysregulation of CCR1 has been implicated in chronic inflammatory diseases, autoimmune disorders, and acute pulmonary inflammation, including hyperinflammatory responses in COVID-19 patients. Natural compounds, with their structural diversity and multifunctional biological activities, present an untapped resource for therapeutic discovery. Among them, Esculin, a coumarin derivative exhibits promising anti-inflammatory and antioxidant properties. However, the precise molecular mechanisms underlying Esculin's interaction with CCR1 remain unclear. Methods: We investigated Esculin, a coumarin derivative with known anti-inflammatory properties, using molecular docking, 200 ns molecular dynamics (MD) simulations, and binding free energy (MMGBSA) analysis. Structural stability, residue-specific interactions, and pharmacokinetic properties (ADMET analysis) were comprehensively evaluated. Results: Molecular docking revealed that Esculin effectively occupied the CCR1 ligand-binding pocket, with a favorable binding energy of -7.4 kcal/mol. MD simulation trajectories demonstrated structural stability of the Esculin-CCR1 complex. Key residues, including Trp90, Tyr93, Lys94, and Tyr113, were identified as critical contributors to binding stability. MMGBSA analysis confirmed energetically favorable interactions (Av. ΔG = -28.32 kcal/mol), with specific residues contributing significantly to the overall binding energy. ADMET analysis highlighted Esculin's optimal pharmacokinetic profile, high bioavailability, non-toxic nature, and absence of mutagenic or cardiotoxic risks. Conclusion: Esculin demonstrates stable and energetically favorable binding with CCR1, suggesting its potential as a therapeutic modulator of CCR1-mediated immune responses. These findings highlight Esculin as a promising candidate for treating CCR1-associated diseases, including COVID-19-induced inflammation and chronic inflammatory conditions. Further in vitro and in vivo validation will be essential to confirm its therapeutic efficacy.