César A. Flores-Sandoval

QSAR, docking, dynamic simulation and quantum mechanics studies to explore the recognition properties of cholinesterase binding sites

A set of 84 known N-aryl-monosubstituted derivatives (42 amides: series 1 and 2, and 42 imides: series 3 an 4, from maleic and succinic anhydrides, respectively) that display inhibitory activity toward both acetylcholinesterase and butyrylcholinesterase (ChEs) was considered for Quantitative structure-activity relationship (QSAR) studies. These QSAR studies employed docking data from both ChEs that were previously submitted to molecular dynamics (MD) simulations. Donepezil and galanthamine stereoisomers were included to analyze their quantum mechanics properties and for validating the docking procedure. Quantum parameters such as frontier orbital energies, dipole moment, molecular volume, atomic charges, bond length and reactivity parameters were measured, as well as partition coefficients, molar refractivity and polarizability were also analyzed. In order to evaluate the obtained equations, four compounds: 1a (4-oxo-4-(phenylamino)butanoic acid), 2a ((2Z)-4-oxo-4-(phenylamino)but-2-enoic acid), 3a (2-phenylcyclopentane-1,3-dione) and 4a (2-phenylcyclopent-4-ene-1,3-dione) were employed as independent data set, using only equations with r(m(test))²>0.5. It was observed that residual values gave low value in almost all series, excepting in series 1 for compounds 3a and 4a, and in series 4 for compounds 1a, 2a and 3a, giving a low value for 4a. Consequently, equations seems to be specific according to the structure of the evaluated compound, that means, series 1 fits better for compound 1a, series 3 or 4 fits better for compounds 3a or 4a. Same behavior was observed in the butyrylcholinesterase (BChE). Therefore, obtained equations in this QSAR study could be employed to calculate the inhibition constant (Ki) value for compounds having a similar structure as N-aryl derivatives described here. The QSAR study showed that bond lengths, molecular electrostatic potential and frontier orbital energies are important in both ChE targets. Docking studies revealed that despite the multiple conformations obtained through MD simulations on both ChEs, the ligand recognition properties were conserved. In fact, the complex formed between ChEs and the best N-aryl compound reproduced the binding mode experimentally reported, where the ligand was coupled into the choline-binding site and stabilized through π-π interactions with Trp82 or Trp86 for BChE and AChE, respectively, suggesting that this compound could be an efficient inhibitor and supporting our model.

Triblock copolymers functionalized with quaternary ammonium salts as dehydrating agents for heavy and extra-heavy crude oils

ABSTRACT Block copolymers PEO-PPO-PEO α,ω-functionalized with tertiary aliphatic or aromatic amines were synthesized to obtain a new type of ammonium salt. The compounds were evaluated as demulsifying agents in extra-heavy and heavy Mexican crude oils, 7.5° and 17.8° API. The grafting at the copolymer ends with trioctylamine and quinoline demonstrated to be the best functionalization for increasing the demulsifying efficiency in both crude oils. It was evidenced, for copolymers functionalized with aliphatic amines, that the length of the alkyl chain of the amine plays an important role in the potential to remove emulsified water. Furthermore, it was observed that higher positive value of log P parameter has a strong correlation with the performance of block copolymers functionalized with aliphatic amines. In the case of aromatic amines, the atomic charge of nitrogen proved to be an important factor to provoke the coalescence of the water drops. Finally, the molecular mass of block copolymer was also evaluated, showing that copolymers with higher are more efficient to remove the water from crude oils with huge amounts of asphaltenes. GRAPHICAL ABSTRACT