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

View ORCID ProfileIoan Bâldea
doi: https://doi.org/10.1101/2022.07.29.502012
Ioan Bâldea
Theoretical Chemistry, Heidelberg University, Im Neuenheimer Feld 229, D-69120 Heidelberg, Germany
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  • For correspondence: ioan.baldea@pci.uni-heidelberg.de
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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 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• (1,1-diphenyl-2-picrylhydrazyl) radicals.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted August 01, 2022.
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Why Ortho- and Para-Hydroxy Metabolites Can Scavenge Free Radicals That the Parent Atorvastatin Cannot? Important Pharmacologic Insight from Quantum Chemistry
Ioan Bâldea
bioRxiv 2022.07.29.502012; doi: https://doi.org/10.1101/2022.07.29.502012
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Why Ortho- and Para-Hydroxy Metabolites Can Scavenge Free Radicals That the Parent Atorvastatin Cannot? Important Pharmacologic Insight from Quantum Chemistry
Ioan Bâldea
bioRxiv 2022.07.29.502012; doi: https://doi.org/10.1101/2022.07.29.502012

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