Descripción del proyecto
Dominios transmembrana como nuevas dianas farmacológicas
Las proteínas de la membrana son importantes dianas farmacológicas contra diversas enfermedades. Sin embargo, la naturaleza de los lugares de unión del ligando de estas proteínas limita la especificidad de los fármacos. Los nuevos datos sobre la interacción de los dominios transmembrana (DTM) con los lípidos de la membrana plasmática han llevado a los investigadores del proyecto financiado con fondos europeos Lipopeutics a investigar el potencial de actuar sobre estas partes de las proteínas con fármacos alostéricos. Utilizando simulaciones de dinámica molecular, el proyecto identificará sitios específicos de unión de lípidos en los DTM y diseñará compuestos capaces de unirse dentro del bolsillo hidrofóbico del DTM, estabilizando así el estado funcional de la proteína.
Objetivo
Membrane proteins constitute a third of the human proteome and their relevance to disease has led these proteins to make up more than half of all current drug targets. However, despite this push to identify agents for membrane proteins, the number of established disease-associated targets are limited. The 'open' and solvent-accessible nature of most membrane protein orthosteric sites often results in limited specificity of potential drugs.
The Trans-Membrane domains (TMD) while displaying greater variability among membrane proteins were however long considered lacking in specific interactions. But significant developments in experimental techniques are now identifying this domain to interact and be actively regulated by the diverse lipid components of the membrane. This Lipopeutics project attempts to determine if the analysis of the protein's Lipid interactions can be a pathway to the development of allosteric drugs targeted at these bilayer-exposed pockets.
Unfolding in three major steps, the project first aims to identify specific lipid binding sites with the TMD through the use of long-timescale coarse-grain Molecular Dynamics simulations. Subsequently, the role of this lipid binding event in the protein's functional modulation is validated through atomistic simulations using the Markov State Modelling approach. Finally, cheminformatic screening is used to design lipid-mimicking compounds that are capable of binding within the hydrophobic pocket and stabilizing specific protein functional states.
Ámbito científico
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Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
100 44 Stockholm
Suecia