Why Ortho- and Para-Hydroxy Metabolites Can Scavenge Free Radicals that the Parent Atorvastatin Cannot? Important Pharmacologic Insight from Quantum Chemistry

TL;DR

This study uses quantum chemistry to explain why hydroxyl metabolites of atorvastatin can scavenge free radicals more effectively than the parent drug, revealing a preferred hydrogen transfer mechanism contrary to common assumptions.

Contribution

It provides the first detailed quantum chemical analysis explaining the antioxidant activity of ATV metabolites and identifies HAT as the dominant radical scavenging pathway.

Findings

Hydroxy metabolites have higher radical scavenging activity than parent ATV.

HAT pathway is thermodynamically preferred for scavenging radicals in methanolic phase.

Quantum correlations challenge naive chemical intuition about bond properties.

Abstract

The pharmaceutical success of atorvastatin (ATV), a widely employed drug against the "bad" cholesterol (LDL) and cardiovascular diseases, traces back to its ability to scavenge free radicals. Unfortunately, information on its antioxidant properties is missing or unreliable. Here, we report detailed quantum chemical results for ATV and its ortho- and para-hydroxy metabolites (o-ATV, p-ATV) in the methanolic phase. They comprise global reactivity indices, bond order indices, and spin densities as well as all relevant enthalpies of reaction (bond dissociation BDE, ionization IP and electron attachment EA, proton detachment PDE and proton affinity PA, and electron transfer ETE). With these properties in hand, we can provide the first theoretical explanation of the experimental finding that, due to their free radical scavenging activity, ATV hydroxy metabolites rather than the parent ATV, have substantial inhibitory effect on LDL and the like. Surprisingly (because it is contrary to the most cases currently known), we unambiguously found that HAT (direct hydrogen atom transfer) rather than SPLET (sequential proton loss electron transfer) or SET-PT (stepwise electron transfer proton transfer) is the thermodynamically preferred pathway by which o-ATV and p-ATV in methanolic phase can scavenge DPPH$^\bullet$ (1,1-diphenyl-2-picrylhydrazyl) radicals. From a quantum chemical perspective, the ATV's species investigated are surprising because of the nontrivial correlations between bond dissociation energies, bond lengths, bond order indices and pertaining stretching frequencies, which do not fit the framework of naive chemical intuition.