University of Helsinki
Supervisor: Henri Xhaard
The ATP binding cassette (ABC) transporters are a family of membrane proteins that carry substrates across lipid bilayers against their concentration gradient by hydrolysing ATP. ABC transporters have an important physiological role in transporting endogenous compounds and xenobiotics (like drugs) and as such members of the efflux family of ABC transporters are mainly responsible for drug resistance. The existence of polymorphic forms of the transporters in different individuals or the fact that metabolites instead of parent compounds are transported makes drug resistance a complex phenomena. Understanding the recognition of small molecules by the efflux transporters is key to design effective therapeutic molecules.
We will screen drug-like compound libraries and establish the chemical profiles for efflux protein transported ligands. The transport assays "traditionally" used measure the consumption of ATP, which is related to the activity of the transporters but is quite indirect. More accurate assays have been recently developed that measure the effect on the transport of either a fluorescent compound or a radioactively labelled compound in reconstituted in-side-out vesicles.
Our goals for this PhD project are: (1) to define classes and mode of action for transported compounds; (2) to understand at the atomistic level the interactions of drugs with transporters; (3) large-scale library screening and QSAR modeling to ascribe predictive model of transport; (4) to understand the specificity across the different efflux transporters (MRP2, MDR1 and BCRP).