Project description
Trans-membrane domains as novel drug targets
Membrane proteins constitute important drug targets against many diseases. However, the nature of the ligand binding sites on these proteins limits the specificity of the drugs, leading to many side effects. Emerging evidence on the interaction of trans-membrane domains (TMD) with plasma membrane lipids has led researchers of the EU-funded Lipopeutics project to investigate the potential of targeting these parts of the proteins with allosteric drugs. Using molecular dynamics simulations, the project will identify specific lipid binding sites within TMDs and design compounds capable of binding within the hydrophobic TMD pocket, stabilising the functional state of the protein.
Objective
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.
Fields of science
Programme(s)
Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
100 44 Stockholm
Sweden