title: DFT study on hydroxy acid-lactone interconversion of statins: The case of fluvastatin.
abstract: Fluvastatin is a member of the HMG-CoA reductase inhibitor family of drugs, commonly referred to as statins. It is generally known that, under physiological conditions, statins are susceptible to pH-dependent interconversion between their active (hydroxy acid) and inactive (lactone) forms. The mechanism of this interconversion, under both acidic and basic conditions, was investigated theoretically using the density functional theory (DFT) method. Regardless of the conditions, the lactone form was always higher in energy by 6-19 kcal mol(-1). However, under basic conditions, the activation barrier for the hydrolysis was significantly lower (9 kcal mol(-1)) than for the reverse reaction (28 kcal mol(-1)), making the lactone form unstable. The activation barriers under acidic conditions were of comparable height in both directions (22 and 28 kcal mol(-1)), making the occurrence of both forms equally probable. Due to the high activation barrier (>40 kcal mol(-1)), a one-step, direct interconversion between the two forms turned out to be unfavourable. Moreover, the potential energy surface of fluvastatin was briefly inspected, revealing relatively small energetic differences (<5 kcal mol(-1)) between the key conformers.
authors.affiliation: Quantum Chemistry Group, Faculty of Chemistry, A. Mickiewicz University, Grunwaldzka 6, 60-780, Poznan, Poland. grabar@man.poznan.pl
authors.forename: Tomasz
authors.initials: T
authors.lastname: Grabarkiewicz
authors.forename: Pawel
authors.initials: P
authors.lastname: Grobelny
authors.forename: Marcin
authors.initials: M
authors.lastname: Hoffmann
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Mielcarek
mesh_terms: D003198:Computer Simulation; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry*; D000077340:Fluvastatin; D006863:Hydrogen-Ion Concentration; D006880:Hydroxy Acids / Q000138:chemical synthesis*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry*; D007211:Indoles / Q000737:chemistry*; D007783:Lactones / Q000138:chemical synthesis*; D008968:Molecular Conformation; D013816:Thermodynamics
chemical_list: D005229:Fatty Acids, Monounsaturated; D006880:Hydroxy Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D007783:Lactones; D000077340:Fluvastatin