Hoffmann Marcin, Nowosielski Marcin
Quantum Chemistry Group, Faculty of Chemistry, A. Mickiewicz University, Grunwaldzka 6, 60-780, Poznan, Poland.
Org Biomol Chem. 2008 Oct 7;6(19):3527-31. doi: 10.1039/b803342k. Epub 2008 Jul 18.
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(-1) activation 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.
阿托伐他汀（ATV）是最知名的HMG-CoA还原酶抑制剂家族成员，与其他他汀类药物一样，会发生pH依赖性的羟酸-内酯相互转化。尽管唯一的活性形式是线性形式，但研究表明，内酯形式的药物相互作用也应予以考虑。使用密度泛函理论（DFT）方法对ATV的内酯化-水解机制进行了理论研究。在轻度酸性和碱性条件下，ATV的内酯形式均不如其羟酸形式稳定。然而，在存在羧酸的情况下，平衡仅略微向内酯一侧移动（底物与产物之间相差4 kcal mol⁻¹），而碱性条件下水解的能量增益为18 kcal mol⁻¹。在酸性和碱性条件下，水解活化能垒分别为19和6 kcal mol⁻¹。由于35 kcal mol⁻¹的活化能垒，我们确定在生理条件下一步相互转化是不利的。所有数据均与先前报道的氟伐他汀（FLV）的类似数据进行了比较，结果表明ATV比FLV更具灵活性，这不仅是因为它具有更多可旋转的碳-碳单键，还因为ATV内酯化-水解的能量垒更低。
