LAUSR

Abstract Elucidating the mechanism of interaction between a drug molecule and its corresponding receptors is of great importance. It had been demonstrated that Propranolol as a β-blocker interacts with β-adrenoreceptors through three different binding sites, including the aromatic group (naphthalene) and the secondary amine and hydroxyl groups of the side chain. In this work we exploited selected computational methods for mimicking such kind of interaction via examining computationally the supramolecular interaction of β-cyclodextrin with Propranolol in Solution. We examined and compared the performances of selected computational approaches, namely SQM(PM3 and PM7), DFT(631G), and ONIOM(DFT,SQM(PM3)) for studying such supramolecular interaction, emphasizing the importance of the contribution of dispersion forces and hydrogen bonding in the mechanism of interaction. The stability of the optimized geometries was evaluated using Atom Centered Density Matrix propagation-Dynamic Simulation (ADMP-DS) method. The appropriateness of the examined methods was validated based on comparison with reported experimental results gathered from the literature. In terms of accuracy, the computational methods employed in this work exhibited notable similarities regarding all molecular and geometrical properties, however, great discrepancy was noted regarding the binding thermodynamic quantities, namely ΔG°, ΔH° and TΔS, as well as the driving forces responsible for the formation and stabilization of the PPL-β-CD inclusion complexes. Interestingly, employing the MOPAC-SQM-PM7 method yielded good agreement with the experimental values of ΔG°, ΔH° and TΔS, with absolute deviations of 1.4, 3.3, and 1.5 kcal.mol-1, respectively, for the β-CD wide-rim inclusion of PPL with substantial reduced computational cost. Utilizing the ADMP-MD method confirmed the stability of the optimized geometries of the inclusion complexes within a time frame of 100 fs with average variations in the total energy and length of selected hydrogen bonds of