Dispersion-corrected DFT calculations and dynamic molecular simulations to investigate conformational stability of...

Lidocaine (LDC) is one of the most important local anaesthesia compounds (LAs), designated to treat acute and chronic pain, especially in clinical applications. In the purpose to improve its lower solubility and bioavailability, numerous researches have been conducted to study the exact mode of association between the LDC molecule and cyclodextrins as drug carriers. Although, the reported structural details on LDC/β-CD and LDC/HP-β-CD inclusion complexes remain largely unexplored. The LDC molecule presents different spatial arrangements inside the hydrophobic cavities of the above-mentioned hosts; either the phenyl moiety or the diethylamino part is totally inserted. Hence, in the present work, we attempt to deepen our understanding about conformational preferences on the binding modes of LDC by investigating the quantum mechanical approach results. The PM3 method combined with the pure corrected functional B97D3 revealed the tendency of LDC to enter its diethylamino inside the host, leaving the rest of molecule externally, and consequently form an inclusion complex with HP-β-CD more stable than with the native β-CD by approximately 12 kcal mol^-1. The probability of partial insertion of LDC is further ascertained by MD simulations investigation running for 500 ns. The trajectory analysis of MD process showed that the diethyl amino fragment is accommodated inside the HP-β-CD's cavity for a significant period (82 % of the simulation time), while it is estimated to be 78 % in the case of LDC/β-CD complex. Moreover, the wave function analysis, based on QTAIM, Reduced Density Gradient (RDG) and 2D Fingerprint, illustrated NCIs interactions and sustained the contribution of numerous van der Waals forces and weaker H-bonds interactions in the stability of studied ICs.