DFT study on hydroxy acid–lactone interconversion of statins: the case of atorvastatin

Atorvastatin (ATV), the best known HMG-CoA reductase inhibitor family member, undergoes pH-dependent hydroxy acid–lactone interconversion similar to other statins. Although the only active form is a linear one, it was shown that drug interactions should also be considered for the lactone. The ATV lactonisation–hydrolysis mechanism was investigated theoretically using the density functional theory (DFT) method. Under both mildly acidic and basic conditions, the ATV lactone form is less stable than its hydroxy acid form. However, in the presence of a carboxylic acid, the equilibrium was only slightly shifted towards the lactone side (4 kcal mol−1 difference between the substrate and the product), while energy gain for the hydrolysis under basic conditions amounts to 18 kcal mol−1. Hydrolysis activation energy barriers were 19 and 6 kcal mol−1, in acidic and basic conditions, respectively. We determined one-step interconversion as unfavourable under physiological conditions due to a 35 kcal mol−1activation energy barrier. All data were compared with analogue ones for fluvastatin (FLV) reported earlier and indicated that ATV is more flexible than FLV, not only due to the fact that it has more rotatable carbon–carbon single bonds, but also because ATV lactonistation–hydrolysis energy barriers are lower.