In the present study, the binding free energy of some classical inhibitors (DMT, DNP, GNT, HUP, THA) with acetylcholinesterase (AChE) is calculated by means of the free energy perturbation (FEP) method based on hybrid quantum mechanics and molecular mechanics (QM/MM) potentials. The results highlight the key role of the van der Waals interaction for the inhibition process, since the contribution of this term to the binding free energy is almost as decisive as the electrostatic one. The analysis of the geometrical parameters and the interaction energy per residue along the QM/MM molecular dynamics (MD) simulations highlights the most relevant interactions in the different AChE-ligand systems, showing that the charged residues with a more prominent contribution to the interaction energy are Asp72 and Glu199, although the relative importance depends on the molecular size of the ligand. A correlation between the binding free energy and the number of cation-π interactions present in the systems has been established, DMT being the most potent inhibitor, capable of forming four cation-π interactions. A layer of water molecules surrounding the inhibitors has been observed, which act as bridges along a network formed by the ligands and the residues of the gorge and also between different residues. Although several hydrogen bonds between ligands and AChE do appear, no significant values of BIEs have been recorded. This behavior can be accounted for by the special features of AChE, such as the presence of several subsites of different natures in the gorge or the existence of several water molecules that act as bridges in the electrostatic interactions.

Hartree-Fock and density functional methods were used to analyze electronic and structural properties of known drugs to evaluate the influence of these data on acetylcholinesterase inhibition. The energies of the frontier orbitals and the distances between the more acidic hydrogen species were investigated to determine their contributions to the activity of a group of acetylcholinesterase inhibitors. Electrostatic potential maps indicated suitable sites for drugs-enzyme interactions. In this study, the structural, electronic and spatial properties of nine drugs with known inhibitory effects on acetylcholinesterase were examined. The data were obtained based on calculations at the B3LYP/6-31 + G(d,p) level. Multivariate principal components analysis was applied to 18 parameters to determine the pharmacophoric profile of acetylcholinesterase inhibitors. Desirable features for acetylcholinesterase inhibitor molecules include aromatic systems or groups that simulate the surface electrostatic potential of aromatic systems and the presence of a sufficient number of hydrogen acceptors and few hydrogen donors. PCA showed that electronic properties, including the HOMO-1 orbital energy, logP and aromatic system quantity, as well as structural data, such as volume, size and H-H distance, are the most significant properties.

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In the present study, the binding free energy of a family of huprines with acetylcholinesterase (AChE) is calculated by means of the free energy perturbation method, based on hybrid quantum mechanics and molecular mechanics potentials. Binding free energy calculations and the analysis of the geometrical parameters highlight the importance of the stereochemistry of huprines in AChE inhibition. Binding isotope effects are calculated to unravel the interactions between ligands and the gorge of AChE. New chemical insights are provided to explain and rationalize the experimental results. A good correlation with the experimental data is found for a family of inhibitors with moderate differences in the enzyme affinity. The analysis of the geometrical parameters and interaction energy per residue reveals that Asp72, Glu199, and His440 contribute significantly to the network of interactions between active site residues, which stabilize the inhibitors in the gorge. It seems that a cooperative effect of the residues of the gorge determines the affinity of the enzyme for these inhibitors, where Asp72, Glu199, and His440 make a prominent contribution.

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A new binuclear copper(II) complex [Cu 2 L 2 (μ-SO 4 )(dmf)] with the 2-acetylpyridinebenzoylhydrazone (HL) ligand was synthesized and characterized by elemental analysis, Fourier transform infrared (FT-IR), ultravioletvisible (UV-Vis), single-crystal X-ray diffraction, density functional theory (DFT), and molecular docking studies. The crystal structure revealed each copper(II) atom coordinated to the NNO chelating system of the anionic hydrazone ligand and a sulfate bridged. The copper ions are connected by a sulfate bridge, which keeps a distance of 3.292(3) Å between the two copper(II) centers. Additionally, only one of the copper(II) atoms is coordinated to the oxygen atom of the N,N-dimethylformamide (dmf) solvent molecule, resulting in two different geometry to each metal center. CuÁÁÁO interactions are observed for the secondary coordination sphere of Cu1 and Cu2 atoms with distances of 2.545(2) and 2.821(3) Å, respectively. Theoretical studies with DFT were performed to optimize the geometry of the complex and investigate its spectroscopic properties supporting the experimental results. Two different approaches were used in computational calculations, the plane wave using Perdew-Burke-Ernzerhof (PBE) functional and the localized basis set using the following functionals: B3LYP, B3PW91, CAM-B3LYP, LC-wPBE, M06-2X, ωB97-XD, PBE1PBE, and HSEH1PBE. The in vitro antibacterial potential of the new complex was evaluated against pathogenic bacteria and fungi and compared with the free ligand. The molecular docking was used to predict the inhibitory activity of the ligand and complex against one Gram-positive bacteria (Enterococcus faecalis), one Gram-negative bacteria (Enterobacter aerogenes), and one fungi (Candida albicans) species.