Особистісні схеми як схильність до розвитку соціальної тривожності

У статті здійснено емпіричне дослідження та розкрито основні особистісні схеми як схильності до розвитку соціальної тривожності у студентської молоді. Запропоновані схеми вказують те, що найбільше соціальна тривожність підживлюється схемами зі сфери втрати зв’язку і прив’язаності, які конкретизуються у схеми емоційної депривації, покинення, скривдження, соціальної ізоляції і дефективності. (The article empirically investigates and reveals the main personal schemes as a tendency to develop social anxiety of students youth. The proposed schemes indicate that in most cases social anxiety is fueled by circuits of communication and attachment loss, which are specified in the schemes of emotional deprivation, abandonment, harassment, social isolation and deficiency.

Role of Acetylcholinesterase in β-Amyloid Aggregation Studied by Accelerated Molecular Dynamics

© 2016, Springer Science+Business Media New York.Mechanisms of Alzheimer’s disease development are still under investigation. It was shown that acetylcholinesterase promotes aggregation of β-amyloid. Accelerated molecular dynamics simulations were performed to investigate molecular mechanisms of this process. Results showed that Aβ is strongly attracted to the surface of acetylcholinesterase and forms stable complexes. It was hypothesized that acetylcholinesterase serves as a nucleation center for propagation of β-amyloid aggregation

Molecular polymorphism of human enzymes as the basis of individual sensitivity to drugs. Supercomputer-assisted modeling as a tool for analysis of structural changes and enzymatic activity of proteins

© 2016, Springer Science+Business Media New York.The nature of individual sensitivity to drugs associated with molecular polymorphism of human enzymes is discussed. The influence of molecular polymorphism on the activity of key human esterases, in particular, cholinesterases and carboxylesterase, responsible for hydrolytic metabolism of ester-containing drugs, is analyzed. A method was developed, which involves supercomputer-assisted modeling as a tool for assessment of molecular mechanism of the impact of point mutations on the catalytic activity of enzymes. This work is a part of a study aimed at elaboration of the concept and methods of personalized medicine

Slow-binding inhibition of acetylcholinesterase by an alkylammonium derivative of 6-methyluracil: Mechanism and possible advantages for myasthenia gravis treatment

© 2016 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.Inhibition of human AChE (acetylcholinesterase) and BChE (butyrylcholinesterase) by an alkylammonium derivative of 6-methyluracil, C-547, a potential drug for the treatment of MG (myasthenia gravis) was studied. Kinetic analysis of AChE inhibition showed that C-547 is a slow-binding inhibitor of type B, i.e. after formation of the initial enzyme•inhibitor complex (Ki = 140 pM), an induced-fit step allows establishment of the final complex (Ki = 22 pM). The estimated koff is low, 0.05 -1 . On the other hand, reversible inhibition of human BChE is a fast-binding process of mixed-type (Ki = 1.77 μM; Ki = 3.17 μM). The crystal structure of mouse AChE complexed with C-547 was solved at 3.13 Å resolution. The complex is stabilized by cation-π , stacking and hydrogenbonding interactions. Molecular dynamics simulations of the binding/dissociation processes of C-547 and C-35 (a noncharged analogue) to mouse and human AChEs were performed. Molecular modelling on mouse and human AChE showed that the slow step results from an enzyme conformational change that allows C-547 to cross the bottleneck in the active-site gorge, followed by formation of tight complex, as observed in the crystal structure. In contrast, the related non-charged compound C-35 is not a slow-binding inhibitor. It does not cross the bottleneck because it is not sensitive to the electrostatic driving force to reach the bottom of the gorge. Thus C-547 is one of the most potent and selective reversible inhibitors of AChE with a long residence time, τ; = 20 min, longer than for other reversible inhibitors used in the treatment of MG. This makes C-547 a promising drug for the treatment of this disease

Macrocyclic derivatives of 6-methyluracil as ligands of the peripheral anionic site of acetylcholinesterase

© the Partner Organisations 2014. Novel pyrimidinophanes possessing two o-nitrobenzylethyldialkylammonium heads bridging with different spacers were prepared. Pyrimidinophanes 2a, 2b and 3 are reversible inhibitors of cholinesterases. They show a very good selectivity for human acetylcholinesterase (AChE), with an inhibitory power 100-200 times higher than for human butyrylcholinesterase (BChE). Docking simulations indicate specific binding of pyrimidinophanes 2a and 4 onto the peripheral anionic site of AChE. Other compounds bind to the active center of AChE as well as to the peripheral anionic site. These compounds are dual binding site inhibitors. Pyrimidinophane 2b and its acyclic counterpart 1 were tested in the animal model of myasthenia gravis and may be considered as valuable candidates for the treatment of pathological muscle weakness syndromes. This journal i