In silico designed microtubule-stabilizer drugs against tauopathy in Alzheimer’s disease

Abstract

Microtubules are the main building blocks of the cytoskeleton that maintain the shape of the cell. Microtubule-associated proteins, such as Tau protein, facilitate their plasticity in cells. Highly phosphorylated Tau has weak affinity to microtubule and, hence, high probability of aggregation into neurofibrillary tangles (tauopathy). Alzheimer’s disease evolves when Tau proteins are abnormally phosphorylated. To prevent tauopathy in Alzheimer’s disease, we designed drugs de novo targeting them in silico to the phosphorylated Tau-microtubule complexes. Our molecular docking (AutoDock, MOE, GOLD) and molecular dynamics (GROMACS, 2019.6) simulation results revealed compound 23 (C12H28N4O5) as a potential drug candidate, since it can bind (-11.1 kcal/mol by AutoDock) and fix not only phosphorylated Tau on the surface of microtubules, but also prevent their aggregation into bundles. In addition, compound 23 has shown its ability to de-bundle already grouped phosphorylated peptides into single pieces.

Communicated by Ramaswamy H. Sarma

Keywords:

• Alzheimer’s disease
• Tau peptide
• microtubule-stabilizer drug-like molecules
• in silico rational drug design
• molecular docking
• molecular dynamics

Disclosure statement

No potential conflict of interest was reported by the authors.

Author contributions

E.S. planned the study, conducted the research, designed the compounds, performed molecular docking and molecular dynamics simulations, analyzed the data, made corresponding figures and tables, drafted and edited the manuscript. T.D. guided the study, participated in manuscript draft, revisions and editing. The authors finalized the manuscript together.

Additional information

Funding

Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) –Project number 3 74031971-TRR 240/Z2.