Discovery of compound candidates for the treatment of allergic diseases: integration of DFT analyses, molecular docking, molecular dynamics simulations, and ADMET profiling.

In this study, a combination of computational analyses (drug similarity, physicochemical properties, pharmacokinetic properties, molecular docking, molecular dynamics simulation, principal component analysis (PCA), free energy landscape (FEL), density functional theory (DFT), and absorption, distribution, metabolism, and excretion (ADMET) analysis) was used to evaluate the efficacy of natural compounds (aloe emodin, fisetin, vitamin D3, β-carotene, berberine, and cinnamic acid) against allergic diseases and compare them with pharmaceuticals such as cetirizine and mizolastine. Elementary molecular structures and electronic properties were determined through DFT calculations accounting for reactivity by natural bond orbital (NBO) and nonlinear optical properties (NLO) analyses. Molecular docking studies were performed on critical proteins interleukin-10 (IL-10), filaggrin, thymic stromal lymphopoietin (TSLP), and high-affinity Fc receptor for immunoglobulin E (FcεRI) to elucidate the energetics of binding and to reveal interaction mechanisms facilitated by hydrophobic and hydrogen bonds. Highlighted in molecular docking, molecular dynamics (MD) simulation analysis of beta carotene and mizolastine was performed for IL-10, TSLP, FcεRI, and filaggrin, respectively. MD simulation revealed that the beta carotene-IL-10 complex exhibited higher structural stability. MD simulation showed that both filaggrin apoprotein and the mizolastine-filaggrin complex maintained their structural stability with consistent root mean square standard deviation, root mean square fluctuation, radius of gyration, and solvent accessible surface area (SASA) values. MD simulation revealed that both TSLP apoprotein and the beta carotene-TSLP complex maintained their stable conformations. MD simulation showed that both the FcεRI apoprotein and the beta carotene-FcεRI complex achieved stable structures with consistent radius of gyration and SASA values. PCA and FEL analyses revealed ligand-induced conformational variability. Although some physicochemical properties require further development, β-carotene, exhibiting very strong protein binding, and vitamin D3, particularly displaying good integration, superior drug-like properties, low toxicity, and good binding affinity, have been identified as promising candidates for the treatment of allergic diseases. This comprehensive approach combines structural chemistry, energetics, and drug discovery to create a powerful model for the rational design of allergy medications.