Analysis of active sites structures of monoamine oxidases A and B and design of a new generation of MAO inhibitors

Información del proyecto

Identificador del acuerdo de subvención: INTAS-1999-00433

Proyecto cerrado

Fecha de inicio 1 Abril 2000

Fecha de finalización 31 Marzo 2003

Financiado con arreglo a

• International Association for the promotion of cooperation with scientists from the independent states of the former Soviet Union (INTAS), 1993-

Coste total

Sin datos

Aportación de la UE

€ 60 000,00

Coordinado por

Faculté Universitaire Notre-Dame de la Paix
Belgium

Objetivo

Monoamine oxidase (MAO; EC1.4.3.4) is a key enzyme involved into catabolism of major monoamine neurtransmitters. It exists in two isoforms, denominated as MAO A and MAO B. Altered MAO activity has been recognised in numerous neuro-psychiatric conditions and MAO A inhibitors are effective antidepressants whereas MAO B inhibitor deprenyl is widely used for the treatment of Parkinson's disease.
MAO is a hydrophobic protein, which readily aggregates after purification and extraction of detergents. This seriously complicates enzyme crystallisation and therefore characterisation of the active site of this enzyme. Molecular biology manipulations, constructing various chimeric proteins can only partially explain differences between MAO A and MAO B with respect to very limited number of selective substrates and inhibitors. Tertiary structure of either isoform remains unknown and so active site structure still requires further characterisation using other approaches.
. In this project we intend:
(a) To evaluate spatial characteristics of active sites of monoamine oxidase A and B using few sets of flexible and rigid competitive inhibitors of MAO;
(b)To determine the role of flavin cofactor and active site thiols in the MAO interaction with these inhibitors;
(c)To develop a model of human MAO A and MAO B;
(d)To develop the new generation of competitive reversible inhibitors with equal efficacy with respect to both type of MAO (MAO A and MAO B).

The results of this research will provide a clearer explanation for basic differences in the substrate specificity and inhibitor selectivity of MAO A and B. Elucidation of fundamental principles for design of new generation of reversible inhibitors with equal efficacy with respect to both MAOs will allow to develop new much more potent drugs for the treatment of neurological disorders. In addition, the information will provide the wisdom necessary to avoid unwanted MAO inhibitory activity in other drugs.
All research teams have constant reliable contacts for at least 3-5 years. They are interested in various aspects of monoamine oxidase and approached employed by each team are complementary to each other. This will promote successful solution of the problem announced in the proposal.

Ámbito científico (EuroSciVoc)

Este proyecto aún no se ha clasificado con EuroSciVoc.
Sugiera los ámbitos científicos que considere más relevantes y ayúdenos a mejorar nuestro servicio de clasificación.

Programa(s)

• IC-INTAS - International Association for the promotion of cooperation with scientists from the independent states of the former Soviet Union (INTAS), 1993-

Tema(s)

• 3 - Chemistry
• OPEN - OPEN Call

Convocatoria de propuestas

Datos no disponibles

Régimen de financiación

Datos no disponibles

Coordinador

Faculté Universitaire Notre-Dame de la Paix

• Aportación de la UE: Sin datos
• Dirección: Rue de Bruxelles 61 ; 5000 Namur ; Bélgica
• Coste total: Sin datos

Participantes (3)

Russian Academy of Medical Sciences

Rusia

• Aportación de la UE: Sin datos
• Dirección: Pogodinskaya street 10 ; 118932 Moscow
• Coste total: Sin datos

Russian Academy of Sciences

Rusia

• Aportación de la UE: Sin datos
• Dirección: Vavilova Street 28 ; 117813 Moscow
• Coste total: Sin datos

University of St. Andrews

Reino Unido

• Aportación de la UE: Sin datos
• Dirección: BMS Building, North Haugh ; KY19 9ST St. Andrews
• Coste total: Sin datos