Exploring Tau Fibril-Disaggregating and Antioxidating Molecules Binding to Membrane-Bound Amyloid Oligomers Using Machine Learning-Enhanced Docking and Molecular Dynamics

Author:

Segura Luthary1ORCID,Santos Natalia2,Flores Rafael3ORCID,Sikazwe Donald3ORCID,McGibbon Miles4ORCID,Blay Vincent5ORCID,Cheng Kwan H.12ORCID

Affiliation:

1. Neuroscience Department, Trinity University, San Antonio, TX 78212, USA

2. Physics Department, Trinity University, San Antonio, TX 78212, USA

3. Pharmaceutical Sciences Department, Feik School of Pharmacy, University of the Incarnate Word, San Antonio, TX 78209, USA

4. Institute of Quantitative Biology, Biochemistry and Biotechnology, University of Edinburgh, Edinburgh EH9 3BF, UK

5. Department of Microbiology and Environmental Toxicology, University of California at Santa Cruz, Santa Cruz, CA 95064, USA

Abstract

Intracellular tau fibrils are sources of neurotoxicity and oxidative stress in Alzheimer’s. Current drug discovery efforts have focused on molecules with tau fibril disaggregation and antioxidation functions. However, recent studies suggest that membrane-bound tau-containing oligomers (mTCOs), smaller and less ordered than tau fibrils, are neurotoxic in the early stage of Alzheimer’s. Whether tau fibril-targeting molecules are effective against mTCOs is unknown. The binding of epigallocatechin-3-gallate (EGCG), CNS-11, and BHT-CNS-11 to in silico mTCOs and experimental tau fibrils was investigated using machine learning-enhanced docking and molecular dynamics simulations. EGCG and CNS-11 have tau fibril disaggregation functions, while the proposed BHT-CNS-11 has potential tau fibril disaggregation and antioxidation functions like EGCG. Our results suggest that the three molecules studied may also bind to mTCOs. The predicted binding probability of EGCG to mTCOs increases with the protein aggregate size. In contrast, the predicted probability of CNS-11 and BHT-CNS-11 binding to the dimeric mTCOs is higher than binding to the tetrameric mTCOs for the homo tau but not for the hetero tau–amylin oligomers. Our results also support the idea that anionic lipids may promote the binding of molecules to mTCOs. We conclude that tau fibril-disaggregating and antioxidating molecules may bind to mTCOs, and that mTCOs may also be useful targets for Alzheimer’s drug design.

Funder

National Institutes of Health

Robert A. Welch Foundation

National Science Foundation

McNair Scholars Progra

Trinity University

Publisher

MDPI AG

Reference68 articles.

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