title: Structure-based optimization and biological evaluation of human 20α-hydroxysteroid dehydrogenase (AKR1C1) salicylic acid-based inhibitors.
abstract: The tertiary structure of the Leu308Val mutant of human 20α-hydroxysteroid dehydrogenase (AKR1C1) in complex with the inhibitor 3,5-dichlorosalicylic acid (DCL) has been determined. Structures and kinetic properties of the wild-type and mutant enzymes indicate that Leu308 is a selectivity determinant for inhibitor binding. The Leu308Val mutation resulted in 13-fold and 3-fold reductions in the inhibitory potencies of DCL and 3-bromo-5-phenylsalicylic acid (BPSA), respectively. The replacement of Leu308 with an alanine resulted in 473-fold and 27-fold reductions in the potencies for DCL and BPSA, respectively. In our attempts to optimize inhibitor potency and selectivity we synthesized 5-substituted 3-chlorosalicylic acid derivatives, of which the most potent compound, 3-chloro-5-phenylsalicylic acid (K(i) = 0.86 nM), was 24-fold more selective for AKR1C1 relative to the structurally similar 3α-hydroxysteroid dehydrogenase (AKR1C2). Furthermore, the compound inhibited the metabolism of progesterone in AKR1C1-overexpressed cells with an IC(50) value equal to 100 nM.
authors.affiliation: Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia. ossama.el-kabbani@monash.edu
authors.forename: Ossama
authors.initials: O
authors.lastname: El-Kabbani
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scammells
authors.forename: Tom
authors.initials: T
authors.lastname: Day
authors.forename: Urmi
authors.initials: U
authors.lastname: Dhagat
authors.forename: Satoshi
authors.initials: S
authors.lastname: Endo
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsunaga
authors.forename: Midori
authors.initials: M
authors.lastname: Soda
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
mesh_terms: D015089:20-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000235:genetics; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D003460:Crystallization; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D020156:Salicylic Acid / Q000737:chemistry* / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D015089:20-Hydroxysteroid Dehydrogenases; C115140:3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase; D020156:Salicylic Acid