HER2 overexpression is linked to aggressive cancers, highlighting the need for potent and selective inhibitors. This study employs a computational approach to design and optimize novel oxazolo-quinazoline derivatives as HER2 inhibitors. A 3D-QSAR model guided the rational modification of ligands, followed by molecular docking to evaluate binding interactions. Molecular dynamics (MD) simulations assessed the stability and conformational behavior of the selected compounds, while ADME and physicochemical predictions ensured their drug-likeness and pharmacokinetic suitability. Among the designed compounds, 3-(2-chloro-4-((2-oxo-1-(pyridin-3-yl)-1,2-dihydrooxazolo[4,5-g]quinazolin-8-yl)amino)phenoxy)propan-1-aminium (A1) and 3-(2-chloro-4-((2-oxo-1-(pyridin-4-yl)-1,2-dihydrooxazolo [4,5-g]quinazolin-8-yl)amino)phenoxy)propan-1-aminium (A4) exhibited strong binding affinities, stable interactions in MD simulations and favorable ADME properties. These compounds share a core oxazolo-quinazoline scaffold linked to a substituted phenoxypropan-1-aminium moiety, with variations in the heterocyclic substituent (pyridine or imidazole) influencing their electronic properties and binding efficiency. A1 emerged as the most promising candidate, balancing strong receptor interactions, pharmacokinetic properties and synthetic feasibility. A synthetic scheme for A1 was proposed to facilitate experimental validation. This study provides critical insights into the rational design of HER2 inhibitors and highlights the therapeutic potential of optimized oxazolo-quinazoline derivatives for targeted cancer therapy.
