Descrizione del progetto
Adoperare i domini transmembrana come nuovi bersagli farmacologici
Le proteine delle membrane rappresentano importanti bersagli farmacologici per combattere molte malattie. Tuttavia, la natura dei siti di legame del ligando presenti su queste proteine limita la specificità dei farmaci dando origine a numerosi effetti collaterali. Prove emergenti sull’interazione dei domini transmembrana (TMD, Trans-Membrane Domain) con i lipidi della membrana plasmatica hanno portato i ricercatori del progetto Lipopeutics, finanziato dall’UE, a esaminare il potenziale derivante dall’intervento su queste parti delle proteine utilizzando farmaci allosterici. Tramite simulazioni di dinamica molecolare, il progetto identificherà specifici siti di legame lipidico all’interno dei TMD e progetterà composti in grado di legarsi all’interno della tasca idrofobica del TMD, stabilizzando lo stato funzionale della proteina.
Obiettivo
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.
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Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
100 44 Stockholm
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