title: Serendipitous fragment-based drug discovery: ketogenic diet metabolites and statins effectively inhibit several carbonic anhydrases.
abstract: Acetoacetic acid and R-3-hydroxy-butyric acid (BHB) are "ketone bodies", metabolites produced during the ketogenic diet. We discovered that they inhibit in the submicromolar-micromolar range several carbonic anhydrase (CA, EC 4.2.1.1) isoforms involved in relevant physiologic processes such as lipogenesis and tumorigenesis. The BHB fragment is also present in the molecules of most statins, widely used drugs for inhibiting cholesterol biosynthesis through the 3-hydroxy-3-methyl-glutaryl-CoA reductase pathway. Three such statins, atorvastatin, fluvastatin and rosuvastatin, showed submicromolar-low nanomolar inhibition of the fifteen human isoforms hCA I-XIV. Our data point out that in addition to their cholesterol lowering properties, these drugs may exert a therapeutic effect by inhibiting lipogenesis through mitochondrial CA inhibition. The statins are also low nanomolar inhibitors of the tumor-associated isoforms CA IX and XII. Based on the BHB/statin scaffolds, antiepileptic, antiobesity and antitumor compounds with higher affinity for the various CA isoforms involved in epileptogenesis (CA VA, VB, VII), lipogenesis (CA III, CA VA, CA VB) and tumorigenesis (CA IX and CA XII) may be designed.
authors.affiliation: BioMediTech and School of Medicine, University of Tampere, and Tampere University Hospital, Tampere, Finland.
authors.forename: Seppo
authors.initials: S
authors.lastname: Parkkila
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Alfonso
authors.initials: A
authors.lastname: Maresca
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Carta
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000494:pharmacology*; D000090:Acetoacetates / Q000494:pharmacology*; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D055423:Diet, Ketogenic; D055808:Drug Discovery; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism
chemical_list: D000090:Acetoacetates; D002257:Carbonic Anhydrase Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C016635:acetoacetic acid; D020155:3-Hydroxybutyric Acid