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 A beta 42 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 A beta 42 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 A beta 42 amyloid fibrils, partly leading to destabilization of the fibrillar structure. Clarifying the molecular determinants of doxycycline binding to A beta 42 may help devise further strategies for structure-based drug design for Alzheimer's disease.

The anti-amyloidogenic action of doxycycline: A molecular dynamics study on the interaction with Aβ42

Gautieri A.;Rigoldi F.;
2019-01-01

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 A beta 42 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 A beta 42 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 A beta 42 amyloid fibrils, partly leading to destabilization of the fibrillar structure. Clarifying the molecular determinants of doxycycline binding to A beta 42 may help devise further strategies for structure-based drug design for Alzheimer's disease.
Alzheimer’s disease; Amyloid-beta protein; Curcumin; Doxycycline; Iododoxorubicin; Molecular dynamics
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11311/1119220
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