Identification of acetylcholinesterase inhibitors and stability analysis of THC@HP-β-CD inclusion complex: A comprehensive computational study.

Complexing medications with cyclodextrins can enhance their solubility and stability. In this study, we investigated the host-guest complexation between Tetrahydrocurcumin (THC) and Hydroxypropyl-β-Cyclodextrin (HP-β-CD) using density functional theory (DFT) at the B3LYP-D3/TPZ level of theory in two possible orientations. To determine the reactive sites in both complexes for electrophilic and nucleophilic attacks, we calculated and interpreted the binding energy, HOMO and LUMO orbitals, global chemical reactivity descriptors, natural bond orbital (NBO) analysis, and Fukui indices. The results indicate that Orientation A is energetically more favorable than Orientation B. Non-covalent interactions (NCI) were analyzed using reduced density gradient (RDG) approaches, providing detailed insights into host-guest interactions, including hydrogen bonding and van der Waals forces. To further assess stability, we conducted 1000 ns molecular dynamics (MD) simulations and analyzed the root mean square deviations (RMSD) for systems containing 1, 2, and 10 complexes. The RMSD analysis confirmed the stability of the systems, with average RMSD values of 2.01, 3.21, and 4.29 Å, respectively. In the second part of this study, we examined the interaction between THC and the target protein Acetylcholinesterase (E.C. 3.1.1.7) with PDB ID 1QTI. Molecular docking was performed to identify the binding modes and interaction energies of the THC-protein complex. Subsequently, 1000 ns MD simulations were conducted to assess the stability and dynamic behavior of the THC-protein complex over an extended period. The analysis provided valuable insights into the binding interactions and stability of THC with the target protein, further confirming its potential as a therapeutic agent.