title: Lipodisks integrated with weak affinity chromatography enable fragment screening of integral membrane proteins.
abstract: Membrane proteins constitute the largest class of drug targets but they present many challenges in drug discovery. Importantly, the discovery of potential drug candidates is hampered by the limited availability of efficient methods for screening drug-protein interactions. In this work we present a novel strategy for rapid identification of molecules capable of binding to a selected membrane protein. An integral membrane protein (human aquaporin-1) was incorporated into planar lipid bilayer disks (lipodisks), which were subsequently covalently coupled to porous derivatized silica and packed into HPLC columns. The obtained affinity columns were used in a typical protocol for fragment screening by weak affinity chromatography (WAC), in which one hit was identified out of a 200 compound collection. The lipodisk-based strategy, which ensures a stable and native-like lipid environment for the protein, is expected to work also with other membrane proteins and screening procedures.
authors.affiliation: Linnaeus University, Department of Chemistry and Biomedical Sciences, SE-39182 Kalmar, Sweden.
authors.forename: Minh-Dao
authors.initials: MD
authors.lastname: Duong-Thi
authors.forename: Maria
authors.initials: M
authors.lastname: Bergström
authors.forename: Katarina
authors.initials: K
authors.lastname: Edwards
authors.forename: Jonny
authors.initials: J
authors.lastname: Eriksson
authors.forename: Sten
authors.initials: S
authors.lastname: Ohlson
authors.forename: Janet To Yiu
authors.initials: JT
authors.lastname: Ying
authors.forename: Jaume
authors.initials: J
authors.lastname: Torres
authors.forename: Víctor Agmo
authors.initials: VA
authors.lastname: Hernández
mesh_terms: D051398:Aquaporin 1 / Q000737:chemistry / Q000378:metabolism; D002846:Chromatography, Affinity / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry*; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D016062:Porosity; D012822:Silicon Dioxide / Q000737:chemistry
chemical_list: D008051:Lipid Bilayers; D008565:Membrane Proteins; D051398:Aquaporin 1; D012822:Silicon Dioxide