Similarities Between the Binding Sites of Monoamine Oxidase (MAO) from Different Species — Is Zebrafish a Useful Model for the Discovery of Novel MAO Inhibitors?

Fierro, Angélica; Montecinos, Alejandro Miranda; Gómez-Molina, Gabriel Núñez Cristobal; Aldeco, Milagros; Edmondson, Dale E.; MarceloVilches-Herrera,; Lühr, Susan; Iturriaga-Vásquez, Patricio; MiguelReyes-Parada,

doi:10.5772/35874

Cited by 10 publications

(14 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2A, Fig. S90, Supplementary data ); four hydrogen bond interactions were observed, one of them between the carbonyl oxygen of the ligand and amino group of Gln215, which has been reported to have a critical role in the orientation and stabilization of the inhibitor binding [33], two hydrogen bonds between C=O of Ala111 and both the hydroxyl at C-4′and hydrogen at C-3′ in the ligand, in addition to a hydrogen bond interaction between C-3 of the ligand and C 4 =O of FAD. A π-π stacking is established between A-ring and Phe352 and between B-ring and Phe208.…”

Section: Resultsmentioning

confidence: 99%

“…S90, Supplementary data). The active site of hMAO-B consists of two separate but jointly operating subdomains, entrance cavity (~290 Å 3 ) and substrate cavity (~420 Å 3 ), the residues Phe168, Leu171, Ile199, and Tyr326 act as “internal gate” between the two cavities [33,34]. Small inhibitors induce Ile199 to rotate into a closed conformation, leading to a dual cavity active site, while bulky inhibitors force Ile199 to the open conformation and fusing the two cavities into one (~700 Å 3 ) [34].…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Monoamine oxidases inhibitors from Colvillea racemosa : Isolation, biological evaluation, and computational study

et al. 2018

View full text Add to dashboard Cite

Bioassay-guided fractionation and chemical investigation of Colvillea racemosa stems led to identification of two new α, β-dihydroxydihydrochalcones, colveol A (1) and colveol B (2) along with fifteen known compounds. The structures were elucidated via interpretation of spectroscopic data. The absolute configurations of the dihydrochalcones 1 and 2 were assigned by a combination of chemical modification and electronic circular dichroism data. The isolated compounds were evaluated for their inhibition activity toward recombinant human monoamine oxidases (rhMAO-A and -B). Compound 1 demonstrated preferential inhibition against hMAO-A isoenzyme (IC 0.62μM, SI 0.02) while S-naringenin (13) and isoliquiritigein (15) demonstrated preferential hMAO-B inhibition (IC 0.27 and 0.51μM, SI 31.77 and 44.69, respectively). Fisetin (11) showed inhibition against hMAO-A with IC value of 4.62μM and no inhibitory activity toward hMAO-B up to 100μM. Molecular docking studies for the most active compounds were conducted to demonstrate the putative binding modes. It suggested that 1 interacts with Gln215, Ala111, Phe352, and Phe208 amino acid residues which have a role in the orientation and stabilization of the inhibitor binding to hMAO-A, while S-naringenin (13) occupies both entrance and substrate cavities and interacts with Tyr326, a critical residue in inhibitor recognition in hMAO-B.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Monoamine oxidases inhibitors from Colvillea racemosa : Isolation, biological evaluation, and computational study

et al. 2018

View full text Add to dashboard Cite

show abstract

“…To evaluate the similarity between the ligand binding sites at the proteins of interest we used the Pocketmatch algorithm [ 49 ]. All aspects involved in binding site comparisons followed the procedure published in the original article describing the algorithm with minor modifications [ 50 , 51 ]. Briefly and as previously described [ 51 ], each binding site was considered as that determined by the residues for which one or more atoms surround a dummy atom (a crystallographic ligand in the original report) at a given distance (distances from 3 Å to 10 Å from the dummy atoms were considered).…”

Section: Methodsmentioning

confidence: 99%

3D similarities between the binding sites of monoaminergic target proteins

et al. 2018

View full text Add to dashboard Cite

The study of binding site similarities can be relevant to understand the interaction of different drugs at several molecular targets. The increasing availability of protein crystal structures and the development of novel algorithms designed to evaluate three-dimensional similarities, represent a great opportunity to explore the existence of electronic and shape features shared by clinically relevant proteins, which could assist drug design and discovery. Proteins involved in the recognition of monoaminergic neurotransmitters, such as monoamine transporters or monoamine oxidases (MAO) have been related to several psychiatric and neurological disorders such as depression or Parkinson’s disease. In this work, we evaluated the possible existence of similarities among the binding sites of the serotonin transporter (SERT), the dopamine transporter (DAT), MAO-A and MAO-B. This study was carried out using molecular simulation methodologies linked to the statistical algorithm PocketMatch, which was modified in order to obtain similarities profiles. Our results show that DAT and SERT exhibit a high degree of 3-D similarities all along the pathway that is presumably involved in the substrate transport process. Distinct differences, on the other hand, were found both at the extracellular and the intracellular ends of the transporters, which might be involved in the selective initial recognition of the corresponding substrate. Similarities were also found between the active (catalytic) site of MAO-A and the extracellular vestibule of SERT (the S2 binding site). These results suggest some degree of structural convergence for these proteins, which have different functions, tissue distribution and genetic origin, but which share the same endogenous ligand (serotonin). Beyond the functional implications, these findings are valuable for the design of both selective and non-selective ligands.

show abstract

“…Lastly, while humans have two MAO subtypes (MAO-A and MAO-B), zebrafish have only one type of MAO, termed as the zMAO ( Arslan and Edmondson, 2010 ). Although no known tertiary protein structure is currently available in the literature, a hypothetical substrate-binding site indicates that the zMAO is functionally more similar to human MAO-A than MAO-B ( Arslan and Edmondson, 2010 ; Fierro et al, 2013 ). Since MAO is very essential as it breaks down important neurotransmitters in the brain and is said to participate in PD pathophysiology, zebrafish studies involving the mechanism of action of this enzyme should be cautiously interpreted.…”

Section: Zebrafish As An Animal Modelmentioning

confidence: 99%

The Promise of the Zebrafish Model for Parkinson’s Disease: Today’s Science and Tomorrow’s Treatment

et al. 2021

View full text Add to dashboard Cite

The second most prevalent neurodegenerative disorder in the elderly is Parkinson’s disease (PD). Its etiology is unclear and there are no available disease-modifying medicines. Therefore, more evidence is required concerning its pathogenesis. The use of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is the basis of most animal models of PD. MPTP is metabolized by monoamine oxidase B (MAO B) to MPP + and induces the loss of dopaminergic neurons in the substantia nigra in mammals. Zebrafish have been commonly used in developmental biology as a model organism, but owing to its perfect mix of properties, it is now emerging as a model for human diseases. Zebrafish (Danio rerio) are cheap and easy to sustain, evolve rapidly, breed transparent embryos in large amounts, and are readily manipulated by different methods, particularly genetic ones. Furthermore, zebrafish are vertebrate species and mammalian findings obtained from zebrafish may be more applicable than those derived from genetic models of invertebrates such as Drosophila melanogaster and Caenorhabditis elegans. The resemblance cannot be taken for granted, however. The goal of the present review article is to highlight the promise of zebrafish as a PD animal model. As its aminergic structures, MPTP mode of action, and PINK1 roles mimic those of mammalians, zebrafish seems to be a viable model for studying PD. The roles of zebrafish MAO, however, vary from those of the two types of MAO present in mammals. The benefits unique to zebrafish, such as the ability to perform large-scale genetic or drug screens, should be exploited in future experiments utilizing zebrafish PD models.

show abstract

Similarities Between the Binding Sites of Monoamine Oxidase (MAO) from Different Species — Is Zebrafish a Useful Model for the Discovery of Novel MAO Inhibitors?

Cited by 10 publications

References 87 publications

Monoamine oxidases inhibitors from Colvillea racemosa : Isolation, biological evaluation, and computational study

Monoamine oxidases inhibitors from Colvillea racemosa : Isolation, biological evaluation, and computational study

3D similarities between the binding sites of monoaminergic target proteins

The Promise of the Zebrafish Model for Parkinson’s Disease: Today’s Science and Tomorrow’s Treatment

Contact Info

Product

Resources

About