Design and Mechanistic Analysis of Novel Antiallergic Agents Using Integrative Computational Approaches Comprising Molecular Docking, DFT, Simulation Dynamics, and Retrosynthesis Studies

The histamine-1 receptor (H1R), a rhodopsin-like G-protein-coupled receptor, is a pivotal mediator of allergic and inflammatory responses. In this study, novel derivatives of diphenhydramine (DPH-1 to DPH-3) and carbinoxamine (CBX-1 to CBX-3) were systematically designed and evaluated as potential H1R antagonists using an integrated computational approach. Virtual screening of a 50-compound library identified eight promising candidates, with physicochemical profiling confirming favorable drug-likeness consistent with Lipinski’s criteria. Molecular docking highlighted DPH-2 and CBX-2 as top candidates, exhibiting strong binding affinities and stable interactions with key H1R residues. Molecular dynamics simulations further confirmed the structural stability and persistence of ligand–receptor interactions under physiological conditions. Density functional theory (DFT/B3LYP/6-31 + G(d)) calculations provided electronic and reactivity profiles of selected ligands. Frontier molecular orbital (FMO) analysis identified a narrow HOMO-LUMO gap (4.95 eV) for CBX-2, correlating with high reactivity, while the ΔEH-L for DPH-2 (5.33 eV) suggested electronic stability. Overall, this integrative strategy identifies DPH-2 and CBX-2 as promising H1R antagonists with optimized pharmacokinetic and binding profiles. AI-assisted retrosynthesis further confirmed feasible synthetic accessibility, underscoring their potential as next-generation anti-allergy therapeutics. Their balanced reactivity, structural stability, and drug-like properties underscore their potential as innovative anti-allergy therapeutics, offering rational framework for future ligand design and optimization.