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The Anti-Amyloidogenic Action of Doxycycline: A Molecular Dynamics Study on the Interaction with Aβ42
Alfonso Gautieri1, Marten Beeg2, Marco Gobbi2
1Biomolecular Engineering Lab, Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133 Milano, Italy. alfonso.gautieri@polimi.it.
Abstract:
The pathological aggregation of amyloidogenic proteins is a hallmark of many neurological diseases, including Alzheimer's disease and prion diseases. We have shown both in vitro and in vivo that doxycycline can inhibit the aggregation of Aβ42 amyloid fibrils and disassemble mature amyloid fibrils. However, the molecular mechanisms of the drug's anti-amyloidogenic property are not understood. In this study, a series of molecular dynamics simulations were performed to explain the molecular mechanism of the destabilization of Aβ42 fibrils by doxycycline and to compare the action of doxycycline with those of iododoxorubicin (a toxic structural homolog of tetracyclines), curcumin (known to have anti-amyloidogenic activity) and gentamicin (an antibiotic with no experimental evidence of anti-amyloidogenic properties). We found that doxycycline tightly binds the exposed hydrophobic amino acids of the Aβ42 amyloid fibrils, partly leading to destabilization of the fibrillar structure. Clarifying the molecular determinants of doxycycline binding to Aβ42 may help devise further strategies for structure-based drug design for Alzheimer's disease.
Insights
Doxycycline inhibits amyloid-beta 42 (Aβ42) fibril formation by binding to exposed hydrophobic residues, destabilizing the structure. This finding offers insights into potential drug design strategies for Alzheimer's disease.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Pathological protein aggregation, particularly amyloidogenic proteins like amyloid-beta 42 (Aβ42), is central to neurodegenerative diseases such as Alzheimer's disease.
- Doxycycline has demonstrated in vitro and in vivo efficacy in inhibiting and disassembling Aβ42 amyloid fibrils.
- The precise molecular mechanisms underlying doxycycline's anti-amyloidogenic effects remain largely unelucidated.
Purpose of the Study:
- To elucidate the molecular mechanism by which doxycycline destabilizes Aβ42 amyloid fibrils.
- To compare the binding and destabilization actions of doxycycline with other compounds: iododoxorubicin, curcumin, and gentamicin.
- To identify molecular determinants of doxycycline's interaction with Aβ42 fibrils for structure-based drug design.
Main Methods:
- Utilized molecular dynamics simulations to investigate the interactions between doxycycline and Aβ42 fibrils.
- Performed comparative analyses of doxycycline against iododoxorubicin, curcumin, and gentamicin.
- Focused on atomic-level interactions and structural changes within the Aβ42 fibril.
Main Results:
- Doxycycline was observed to bind tightly to exposed hydrophobic amino acid residues on the Aβ42 amyloid fibrils.
- This specific binding interaction contributes to the partial destabilization of the fibrillar structure.
- Comparative simulations provided insights into the specificity of doxycycline's anti-amyloidogenic action.
Conclusions:
- Doxycycline's anti-amyloidogenic activity is mediated by its binding to hydrophobic regions of Aβ42 fibrils, leading to structural destabilization.
- Understanding these molecular interactions is crucial for developing targeted therapies for Alzheimer's disease.
- Further research into structure-based drug design leveraging these findings is warranted.
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