Biomolecular Engineering Lab, Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133 Milano, Italy.
Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milano, Italy.
Int J Mol Sci. 2019 Sep 19;20(18):4641. doi: 10.3390/ijms20184641.
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.
淀粉样蛋白原纤维的病理性聚集是许多神经退行性疾病的特征，包括阿尔茨海默病和朊病毒病。我们已经在体外和体内证明，强力霉素可以抑制 Aβ42 淀粉样纤维的聚集并使其解聚。然而，该药物抗淀粉样形成特性的分子机制尚不清楚。在这项研究中，进行了一系列分子动力学模拟，以解释强力霉素使 Aβ42 纤维解聚的分子机制，并比较强力霉素与碘脱氧土霉素（四环素的有毒结构类似物）、姜黄素（已知具有抗淀粉样形成活性）和庆大霉素（一种没有抗淀粉样形成特性的实验证据的抗生素）的作用。我们发现强力霉素紧密结合 Aβ42 淀粉样纤维的暴露疏水性氨基酸，部分导致纤维结构的不稳定性。阐明强力霉素与 Aβ42 结合的分子决定因素可能有助于设计基于结构的阿尔茨海默病药物设计的进一步策略。
