Naslov
Irreversible inhibition of monoamine oxidase B enzyme. A computational insight

Autori
Tandarić, Tana ; Vianello, Robert

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Computational Chemistry Day : Book of Abstracts / - Zagreb : Prirodoslovno-matematički fakultet Sveučilišta u Zagrebu, 2018, 32-32

ISBN
978-953-6076-45-1

Skup
Computational Chemistry Day 2018

Mjesto i datum
Zagreb, Hrvatska, 12.05.2018

Vrsta sudjelovanja
Poster

Vrsta recenzije
Domaća recenzija

Ključne riječi
monoamine oxidase ; inhibitors ; density functional theory ; molecular dynamics

Sažetak
Monoamine oxidases A and B (MAO A and B) are mammalian flavoenzymes responsable for regulation of amine neurotransmiter levels. This enzymes represent main pharmacological target for threatment of depression and neurodegenerative diseases. Two isoform of this enzyme are present in human body, MAO A and MAO B, which share about 70% of the identity in the primary sequence, but show significant differences in substrate selectivity and inhibitor specificity and in particular. Focus of this work are selective irreversible inhibitors of MAO B, selegiline and rasagiline, widely used in treatment of symptoms of Parkinson and Alzheimer disease. Both inhibitors form covalent bond with organic cofactor flavin adenine dinucleotide (FAD). In that way they prevent MAO B enzyme's further catalytic activity. Here, we used a molecular dynamics (MD) simulations, to simulate 300 ns of interaction of MAO B with both inhibitors. It is shown that Tyr398 and Tyr435 form aromatic cage responsable for interaction with aromatic part of inhibitor. Ile199 is characterized as structurally responsible for the selectivity of the inhibitor, which confirms the experimentally obtained results. Aromatic interactions of the inhibitors with the aromatic cage amino acids as well as the hydrogen bonds between the inhibitors and the flavin cofactor carbonyl oxygen O8 orient the inhibitors in a favorable position for the reaction leading to covalent binding of the FAD inhibitor. Using MM-PBSA tools, free binding energy values were obtained. The results show that selegiline binds better than rasagiline by 1.4 kcal / mol which is consistent with experimental IC50 values. Quantum-chemical analysis within the enzyme cluster model showed that MAO inhibition proceeds troughtthe 4-step reaction, with the first step determining the total reaction rate, in which FAD cleaves the hydride ion from the α-methylene group of the substrate in complete analogy with the MAO catalytic mechanism. The resulting reaction profiles and the final structure inhibited by the enzyme are in excellent agreement with the experimental data. The results obtained are of great importance for the development of new and more effective MAO B inhibitors for clinical use.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

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