Mapping the binding site of salbutamol using potential energy surfaces: revisiting the three-point interaction model

Abstract

For the first time, the conformational potential energy surface (PES) of salbutamol within the binding pocket of the β2-adrenergic receptor is reported, explicitly including environmental effects under biologically relevant conditions. A multilevel computational strategy combining molecular dynamics, molecular mechanics, semi-empirical methods, and density functional theory is employed to characterize the ligand conformational space and evaluate the capabilities and limitations of each approach. The resulting conformational PESs provide a detailed visualization of receptor topography for each enantiomer, revealing favorable and unfavorable regions for complex formation, as well as critical points and interconversion pathways not accessible through conventional analyses. Quantum Theory of Atoms in Molecules calculations are used to analyze the intermolecular interactions governing complex stabilization. Salbutamol is selected as a model chiral drug due to the distinct pharmacological behavior of its enantiomers. The results offer molecular-level insight into their stereoelectronic properties and support the Easson–Stedman three-point attachment model.