Discovery of natural dual inhibitors from ZINC database targeting thymic stromal lymphopoietin (TSLP) and interleukin-33 (IL-33) as potential anti-allergy agents

Allergic diseases, affecting millions worldwide, have shown a progressive increase in recent years. Existing anti-allergy drugs primarily target symptoms and downstream reactions, necessitating the exploration of novel therapeutics addressing the root causes in the allergy pathway. Thymic stromal lymphopoietin (TSLP) and interleukin-33 (IL-33), classified as upstream cytokines, play pivotal roles in initiating type-2 immunity and are implicated in allergic diseases. However, small molecule antagonists for both TSLP and IL-33 proteins are still in early development and not yet available as treatments for allergic diseases. This study focuses on identifying natural small molecules that can inhibit both TSLP and IL-33 proteins. The study employed structure-based virtual screening to identify potential dual inhibitors of TSLP and IL-33 from the ZINC database. Through the use of Autodock Vina in PyRx software, virtual screening was conducted to predict the binding mode and binding affinity of these compounds. Molecular dynamics simulations utilizing GROMACS and binding free energy calculations (MM/PBSA) were performed to evaluate the stability and strength of interactions between the identified compounds and the target proteins. Additionally, bioavailability and toxicity analyses were carried out to evaluate the safety and pharmacokinetic properties of the compounds. The study successfully pinpointed three promising compounds, namely ZINC01105767 and ZINC08764679 (fused heterocyclic compounds), and ZINC33833100 (a limonin analogue), as potential dual inhibitors of both TSLP and IL-33 proteins. Molecular dynamics simulations confirmed the structural stability of these complexes, and the analysis of RMSD, RMSF, Rg, and SASA indicated strong interactions. Furthermore, the bioavailability analysis revealed drug-like properties, and toxicity analysis suggested that the compounds are non-mutagenic and non-tumorigenic. ZINC01105767, ZINC08764679, and ZINC33833100 represent promising lead candidates for the treatment of allergic diseases, particularly being heterocyclic compounds with benzoxalyl coumarin, and chromone moieties, which have shown effectiveness in allergic disease treatment.The comprehensive computational analysis provides valuable insights into the structural stability, structural integrity, compactness, folding properties and safety profiles of these compounds, highlighting their potential as anti-allergy agents. Among three dual candidate inhibitors, based on the MM/PBSA based binding free energy analysis, ZINC01105767 emerged as the most promising dual inhibitor, demonstrating the strongest binding affinity with a binding free energy of −43.31 kcal/mol in case of TSLP and −29.87 kcal/mol in case of IL-33. This suggests a potent interaction with both TSLP and IL-33 proteins, indicating its potential as a dual inhibitor targeting these pathways simultaneously. This study paves the way for further investigations and experimental validations, ultimately contributing to the development of more effective therapies for allergic diseases.