Electronic structure and PCA analysis of covalent and non-covalent acetylcholinesterase inhibitors

Abstract

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.

Novel phytochemical–antibiotic conjugates as multitarget inhibitors of Pseudomononas aeruginosa GyrB/ParE and DHFR

“…Additionally, the MEP is a useful descriptor for understanding electrophilic/nucleophilic sites as well as hydrogen bonding interactions. In general, the negative potential sites (red color in Figure 3) of MEP represent regions of electrophilic reactivity and interaction through π-π bonding with the aromatic systems of interacting enzyme residues, while positive potential sites (blue color in Figure 3) represent regions of nucleophilic reactivity 46. As expected, the MEP maps of all the compounds (Figure 3C), clearly show the presence of both a positive potential site and a negative potential site around the hydroxyl groups in the aromatic ring of the phytochemicals, suggesting that these hydroxyl groups can act as both hydrogen bond donor and acceptor elements, indicating their participation in hydrogen bond interactions with hydroxyl and carbonyl groups of key active site residues in GyrB (Asp75, Thr167, Tyr111, and water molecule), ParE (Asp68, Glu45, and water molecule) and DHFR (Asp30, Ile8, Tyr110, and Ile104) enzymes.…”

Pharmacophoric Profile: Design of New Potential Drugs with PCA Analysis

“…PCA has been used to find new potential molecules in a series of biological systems (Carotti et al, 2003;de Paula et al, 2009;Nascimento, et al, 2011). It is a method abundantly used in a lot of multivariate analysis (Jolliffe, 2002).…”

“…PCA have been used to find new potential molecules in a series of biological systems (Carotti, 2003, de Paula, 2009de Paula, 2007;Li, 2009;Nascimento, 2011;Nascimento, 2008;Rocha, 2011;Steindl, 2005). A methodology based on PCA for the pharmacophore identification of the acetylcholinesterase inhibitors (AChEI) was recently used (de Paula, 2009;de Paula, 2007;Fang, 2011;Nascimento, 2011;Nascimento, 2008).…”

“…A methodology based on PCA for the pharmacophore identification of the acetylcholinesterase inhibitors (AChEI) was recently used (de Paula, 2009;de Paula, 2007;Fang, 2011;Nascimento, 2011;Nascimento, 2008). In this chapter the electronic, structural, topological and chemical properties of studied molecules, were taken from the theoretical procedures and related to the activity by means of the multivariate analysis PCs that provides the pharmacophoric profile of these AChEIs.…”

Estudo do mecanismo de ação das moléculas agonistas e antagonistas para o tratamento do mal de Alzheimer e da depressão

“…Para uma avaliação mais detalhada de quais propriedades das MAOIs estão relacionadas com a ação inibitória da AChE foram confrontadas propriedades de 11 drogas com ação inibitória sobre a AChE, além dos NTs, e das 10 MAOIS. 174,175 A primeira PCA ( Tabela 13) As diferenças observadas entre os intervalos de 10 a 50 ps são de 5,0 kcal mol -1 (GNT), 4,7 kcal mol -1 (HUP) e 3,2 kcal mol -1 (ACh), enquanto que as variações dos valores de energia para os tempos de simulação de 50 ps a 100ps se reduzem a 1,8 kcal mol -1 (GNT), 1,6 kcal mol -1 (HUP) e 0,7 kcal mol -1 (ACh Ki 105,177,179,181,182 , (b) Ki 105,177,179,181 , (c) Ki 105,177,181,182 .…”