The Anti-Amyloidogenic Action of Doxycycline: A Molecular Dynamics Study on the Interaction with Aß42.

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 Aß42 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 Aß42 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 Aß42 amyloid fibrils, partly leading to destabilization of the fibrillar structure. Clarifying the molecular determinants of doxycycline binding to Aß42 may help devise further strategies for structure-based drug design for Alzheimer's disease.