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Computational Studies of the Biogenic Amines of the Brain for Targeting Neurological Diseases

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Computational study of the molecular interactions in the brain

A European project carried out computational research to determine how manipulating the functions of monoamine neurotransmitters (MNs) could be used for the treatment of neurological diseases.

Fundamental Research

Monoaminergic systems (MSs) are networks of neurons utilising MNs to regulate important cognitive processes. MNs are neuromodulators that contain an amino group and are derived from aromatic amino acids - phenylalanine, tyrosine, tryptophan, as well as thyroid hormones. Brain MSs are involved in the aetiology of various neurodegenerative diseases. The EU-funded COMPBAND (Computational studies of the biogenic amines of the brain for targeting neurological diseases) project focused on two aspects of MSs. The first was monoamine oxidase enzymes (MAOs) that regulate amine levels in the synaptic region. The second represented histamine H2 receptor, which binds the biogenic amine histamine as its primary endogenous ligand. The project research elucidated the precise molecular mechanism underlying MAO catalytic activity and demonstrated the feasibility of the newly proposed two-step hydride transfer mechanism. In particular, it was shown that both A and B MAO isoforms operate by the same hydride mechanism. This achievement is important in terms of developing new target molecules as MAO inhibitors. MAO A and B isoforms have very different substrate affinities and inhibitor sensitivities. MAO A inhibitors are able to raise serotonin concentrations, making them useful in depression treatment. MAO B inhibitors decrease dopamine degradation and improve motor control in patients with Parkinson disease. Thus, project insights might be useful for rational modification of MAO, providing guidelines for designing more potent and selective MAO inhibitors. Project members conducted an experimental and computational study monitoring the effects of deuteration on the binding affinities of the histamine H2 receptor towards an antagonist and three agonists. Deuteration-induced changes in the length and strength of the hydrogen bonds did not significantly affect the binding of the antagonist, while the affinities of all agonists were changed. The computational study involved the construction of a homology model of the H2 receptor and quantum chemical modelling of the binding free energies with included empirical quantisation of proton motion. The predicted overall binding of histamine and its deuterated analogue was in line with the experimental values. In conclusion, project analysis can be applied in developing strategies for the prevention and treatment of neurodegeneration. In particular, it might aid in the building of an overall kinetic molecular model of neurodegeneration.


Monoaminergic systems, neurodegenerative disease, COMPBAND, monoamine oxidase, histamine H2 receptor

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