Aromatic Regions Govern the Recognition of NADPH Oxidase Inhibitors as Diapocynin and its Analogues.

Oxidative stress is related to the pathogenesis and progress of several human diseases. NADPH oxidase (NOX), and mainly the NOX2 isoform, produces superoxide anions (O2•- ). To date, it is known that NOX2 can be inhibited by preventing the assembly of its subunits, p47phox and p22phox. In this work, we analyzed the binding to NOX2 of the apocynin dimer, diapocynin (C1), a known NOX2 inhibitor, and of 18 designed compounds (C2-C19) which have chemical relationships to C1, by in silico methods employing a p47phox structure from the Protein Data Bank (PDB code: 1WLP). C1 and six of the designed compounds were recognized in the region where p22phox binds to p47phox and makes π-π interactions principally with W193, W263, and Y279, which form an aromatic-rich region. C8 was chosen as the best compound according to the in silico studies and was synthesized and evaluated in vitro. C8 was able to prevent the production of reactive oxygen species (ROS) similar to C1. In conclusion, targeting the aromatic region of p47phox through π-interactions is important for inhibiting NOX activity.

Common behavior of the critical properties of the 2D and 3D square-well fluids.

We have analyzed the behavior of the critical properties and second virial coefficient of the square well fluids in two (2D) and three dimensions (3D) as a function of the interaction range. In both systems, the critical density shows an oscillating-like behavior as the interaction range increases. The second virial coefficient evaluated at the critical temperature as a function of the interaction range shows a general behavior for both cases, and quite surprisingly, there is a minimum of this parameter, for the 2D and 3D fluids, located approximately at the same interaction range. These findings are discussed in terms of the structure of the fluids, via the analysis of the radial distribution function evaluated at the critical point.

Docking and quantum mechanic studies on cholinesterases and their inhibitors.

Docking studies and density functional theory (DFT) calculations were made for 88 N-aryl derivatives and for some acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) residues. Based on this information, some compounds were synthesized and tested kinetically in vitro as AChE inhibitors. Finally, some chemical properties of the N-aryl derivatives were calculated: partition coefficient (pi) and molecular electrostatic potentials (MESPs) whereas their electronic effects (rho) were taken from the literature. The results showed that all compounds act inside the AChE gorge, making pi-pi interactions and hydrogen bonds with Trp86 and Ser203 and by high HOMO energies of Ser2003 and high LUMO energies of N-aryl derivatives. These theoretical calculations for AChE are in agreement with the experimental data, whereas such calculations for BChE do not show the same behavior which could be due to in spite of both cholinesterase enzymes displaying similar functional activities they do possess important structural differences at their catalystic sites.

Ex vivo anticholinesterase activity of benzoic acid derivatives.

p-Aminobenzoic acid (p-ABA) derivatives were evaluated as acetylcholinesterase inhibitors (AChEIs). Finding a correlation between AChE activity with the partition coefficient (log P) and the highest occupied molecular orbital (HOMO) energy of the compounds.