Structure-based Virtual Screening of Natural Compounds as Potential Anti-Allergy Agents Against Cytokine Alarmins (TSLP and IL-33)

Background: Allergic diseases are turning into an expanding occurrence around the globe, imposing a socioeconomic burden, causing grimness and even death. Allergen encounter initiates the influx of TH2 cells, triggering the production of TH2 associated cytokines (IL-4, IL-5, and IL-13), which in turn promotes the detrimental allergic inflammation associated with asthma, allergic rhinitis, food allergy, urticaria, atopic eczema, and anaphylaxis. Cytokine alarmins (TSLP and IL-33) produced by epithelial cells play important roles in the promotion of TH2 cell development and the initiation of allergic pathogenesis. Objective: To target cytokine alarmins (TSLP and IL-33) as novel therapeutic proteins, using natural compounds as a potential cure at an early stage of allergic diseases. Methods: Structure-based virtual screening of two large natural compounds databases (Universal Natural product Database (UNPD) and ZINC natural product database) was conducted for the identification of TSLP and IL-33 inhibitors using Autodock Vina followed by rescoring of the hit compounds. using Autodock 4.2 software. In silico physicochemical, pharmacokinetic, and toxicity analyses were conducted to assess the drug-like properties of the hit compounds. The binding mode stability of UNPD116849, ZINC01448143, and ZINC04096134 in the binding pocket of TSLP and IL-33 was probed by all-atom 50 ns molecular dynamics simulation. Results: Five natural compounds (UNPD111, UNPD116849, ZINC01448143, ZINC15957528, and ZINC04096134) containing different structural moieties (steroidal, chromone, benzodioxole, and indole) were identified to inhibit TSLP and IL-33, with limonin (ZINC04096134) found to demonstrate dual inhibitory activity potential. These compounds were found to be drug-like and toxicity-free using in silico Absorption, Distribution, Metabolism, Elimination, and Toxicity (ADME-T) prediction methods. Taken together, this study suggests the dual inhibition potential of limonin (ZINC04096134) against the cytokine alarmins. Conclusion: Five natural compounds with diverse structural moieties (steroidal, chromone, benzodioxole, and indole) were virtually identified as hit compounds against cytokine alarmins (TSLP and IL-33), with limonin showing dual inhibitory potential.