title: Evaluation of solvent accessibility epitopes for different dehydrogenase inhibitors.
abstract: Knowledge about the orientation of ligands or inhibitors bound to a protein is vital for the development of new drugs. It was recently shown that solvent accessibility epitopes for protein ligands can be mapped by transferring magnetization from water molecules to the ligand to derive the ligand orientation. This is based on the fact that NMR signals of ligands arising from magnetization transferred from solvent molecules via the protein have a different sign from those arising from direct magnetization transfer from bulk water. Herein we critically evaluate the applicability of solvent accessibility mapping to derive binding orientations for ligands of two dehydrogenases (AKR1C3 and HSD17beta1) with very different binding pockets, including complexes in which the ligand is buried more deeply inside the protein. We also evaluate the possibility of using co-solvents, such as DMSO, for magnetization transfer.
authors.affiliation: University of Birmingham, Vincent Drive, Edgbaston, Birmingham B152TT, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Ludwig
authors.forename: Paulus J A
authors.initials: PJ
authors.lastname: Michiels
authors.forename: Alessia
authors.initials: A
authors.lastname: Lodi
authors.forename: John
authors.initials: J
authors.lastname: Ride
authors.forename: Chris
authors.initials: C
authors.lastname: Bunce
authors.forename: Ulrich L
authors.initials: UL
authors.lastname: Günther
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000074425:Aldo-Keto Reductase Family 1 Member C3; D001665:Binding Sites / Q000187:drug effects; D004121:Dimethyl Sulfoxide / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D000939:Epitopes / Q000737:chemistry*; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007213:Indomethacin / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy / Q000379:methods / Q000592:standards; D008280:Magnetics; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D012015:Reference Standards; D012997:Solvents / Q000737:chemistry; D013499:Surface Properties; D014867:Water / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D000939:Epitopes; D005419:Flavonoids; D008024:Ligands; D012997:Solvents; D014867:Water; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; D004960:Estradiol Dehydrogenases; C513331:HSD17B1 protein, human; D007213:Indomethacin; D004121:Dimethyl Sulfoxide