Affiliations: [a]
Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA
| [b]
Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH, USA
Correspondence:
[*]
Correspondence to: Jie Gao, Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA. Tel.: +1 614 293 8915; E-mail: Jie.Gao@osumc.edu.; Junmei Wang, Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA. Tel.: +1 412 383 3268; E-mail: junmei.wang@pitt.edu.
Abstract: Background:Tau assembly produces soluble oligomers and insoluble neurofibrillary tangles, which are neurotoxic to the brain and associated with Alzheimer’s and Parkinson’s diseases. Therefore, preventing tau aggregation is a promising therapy for those neurodegenerative disorders. Objective:The aim of this study was to develop a joint computational/cell-based oligomerization protocol for screening inhibitors of tau assembly. Methods:Virtual oligomerization inhibition (VOI) experiment using molecular dynamics simulation was performed to screen potential oligomerization inhibitors of PHF6 hexapeptide. Tau seeding assay, which is directly related to the outcome of therapeutic intervention, was carried out to confirm a ligand’s ability in inhibiting tau assembly formation. Results:Our protocol was tested on two known compounds, EGCG and Blarcamesine. EGCG inhibited both the aggregation of PHF6 peptide in VOI and tau assembly in tau seeding assay, while Blarcamesine was not a good inhibitor at the two tasks. We also pointed out that good binding affinity to tau aggregates is needed, but not sufficient for a ligand to become a good inhibitor of tau oligomerization. Conclusion:VOI goes beyond traditional computational inhibitor screening of amyloid aggregation by directly examining the inhibitory ability of a ligand to tau oligomerization. Comparing with the traditional biochemical assays, tau seeding activities in cells is a better indicator for the outcome of a therapeutic intervention. Our hybrid protocol has been successfully validated. It can effectively and efficiently identify the inhibitors of amyloid oligomerization/aggregation processes, thus, facilitate to the drug development of tau-related neurodegenerative diseases.
Keywords: Aggregation, EGCG, MD simulation, oligomerization, PHF6, tau protein
