Different positron emission tomography tau tracers bind to multiple binding sites on the tau fibril: insight from computational modeling
Open accessAbstract
Using the recently reported cryo-EM structure for the tau fibril [ Fitzpatrick et al. (2017) Nature 547, 185-190 ], which is a potential target concerning Alzheimer's disease, we present the first molecular modeling studies on its interaction with various positron emission tomography (PET) tracers. Experimentally, based on the binding assay studies, at least three different high-affinity binding sites have been reported for tracers in the tau fibril. Herein, through integrated modeling using molecular docking, molecular dynamics, and binding free energy calculations, we provide insight into the binding patterns of various tracers to the tau fibril. We suggest that there are four different high-affinity binding sites available for many of the studied tracers showing varying binding affinity to different binding sites. Thus, PBB3 binds most strongly to site 4, and interestingly, this site is not a preferable site for any other tracers. For THK5351, our data show that it strongly binds to sites 3 and 1, the former one being more preferable. We also find that MK6240 and T807 bind to site 1 specifically. The modeling data also give some insight into whether a tracer bound to a specific site can be replaced by others or not. For example, the displacement of T807 by PBB3 as reported experimentally can also be explained and attributed to the larger binding affinity of the latter compound in all binding sites. The binding free energy results explain very well the small binding affinity of THK523 compared to all the aryl quinoline moieties containing THK tracers. The ability of certain tau tracers, like FDDNP and THK523, to bind to amyloid fibrils has also been investigated. Furthermore, such off-target interaction of tau tracers with amyloid beta fibrils has been validated using a quantum mechanical fragmentation approach.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
18F-T807 is the most advanced tau PET tracer in terms of its investigation in vivo, with studies completed in numerous tauopathies including AD and PSP.
“18F-T807 is the most advanced tau PET tracer in terms of its investigation in vivo, with studies completed in numerous tauopathies including AD and PSP”
From Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models (2019) · cites this paper as Murugan et al., 2018
Cites
VMD: visual molecular dynamics
Humphrey, W., Dalke, A., & Schulten, K. (1996) · Journal of Molecular Graphics · doi:10.1016/0263-7855(96)00018-5 · Cited by 66,952 · see citing works
Molecular dynamics with coupling to an external bath
Berendsen, H. J. C., Postma, J. P. M., van Gunsteren, W. F., DiNola, A., & Haak, J. R. (1984) · The Journal of Chemical Physics · doi:10.1063/1.448118 · Cited by 30,626 · see citing works
A smooth particle mesh Ewald method
Essmann, U., Perera, L., Berkowitz, M., Darden, T., Lee, H.-C., & Pedersen, L. (1995) · The Journal of Chemical Physics · doi:10.1063/1.470117 · Cited by 21,329 · see citing works
Ryckaert, J., Ciccotti, G., & Berendsen, H. (1977) · Journal of Computational Physics · doi:10.1016/0021-9991(77)90098-5 · Cited by 19,525 · see citing works
Development and testing of a general amber force field
Wang, J.-M., Wolf, R., Caldwell, J., Kollman, P., & Case, D. (2004) · Journal of Computational Chemistry · doi:10.1002/jcc.20035 · Cited by 18,318 · see citing works
Kollman, P. A., Massova, I., Reyes, C., Kuhn, B., Huo, S., Chong, L., Lee, M., Lee, T., Duan, Y., Wang, W., et al. (2000) · Accounts of Chemical Research · doi:10.1021/ar000033j · Cited by 4,978 · see citing works
Breneman, C. M., & Wiberg, K. B. (1990) · Journal of Computational Chemistry · doi:10.1002/jcc.540110311 · Cited by 4,866 · see citing works
MMPBSA.py : An Efficient Program for End-State Free Energy Calculations
Miller, B. R., McGee, T. D., Swails, J., Homeyer, N., Gohlke, H., & Roitberg, A. E. (2012) · Journal of Chemical Theory and Computation · doi:10.1021/ct300418h · Cited by 4,664 · see citing works
Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease
Arriagada, P. V., Growdon, J. H., Hedley-Whyte, E. T., & Hyman, B. T. (1992) · Neurology · doi:10.1212/wnl.42.3.631 · Cited by 2,668 · see citing works
Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders
Ballatore, C., Lee, V. M.-Y., & Trojanowski, J. Q. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2194 · Cited by 2,174 · see citing works
Cryo-EM structures of tau filaments from Alzheimer’s disease
Fitzpatrick, A. W. P., Falcon, B., He, S., Murzin, A. G., Murshudov, G., Garringer, H. J., Crowther, R. A., Ghetti, B., Goedert, M., & Scheres, S. H. W. (2017) · Nature · doi:10.1038/nature23002 · Cited by 2,061 · see citing works
3D structure of Alzheimer's amyloid-β(1–42) fibrils
Lührs, T., Ritter, C., Adrian, M., Riek-Loher, D., Bohrmann, B., Döbeli, H., Schubert, D. A., & Riek, R. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506723102 · Cited by 2,001 · see citing works
Fibril structure of amyloid-β(1–42) by cryo–electron microscopy
Gremer, L., Schölzel, D., Schenk, C., Reinartz, E., Labahn, J., Ravelli, R. B. G., Tusche, M., López‐Iglesias, C., Hoyer, W., Heise, H., et al. (2017) · Science · doi:10.1126/science.aao2825 · Cited by 1,031 · see citing works
Hohenstein, E., Chill, S. T., & Sherrill, C. (2008) · Journal of Chemical Theory and Computation · doi:10.1021/ct800308k · Cited by 810 · see citing works
Maruyama, M., Shimada, H., Suhara, T., Shinotoh, H., Ji, B., Maeda, J., Zhang, M.-R., Trojanowski, J. Q., Lee, V. M.-Y., Ono, M., et al. (2013) · Neuron · doi:10.1016/j.neuron.2013.07.037 · Cited by 760 · see citing works
Buchhave, P. (2012) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2011.155 · Cited by 664 · see citing works
Xia, C., Arteaga, J., Chen, G., Gangadharmath, U., Gomez, L. F., Kasi, D., Lam, C., Liang, Q., Liu, C., Mocharla, V. P., et al. (2013) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2012.11.008 · Cited by 605 · see citing works
Kirschner, D. A., Abraham, C., & Selkoe, D. J. (1986) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.83.2.503 · Cited by 517 · see citing works
Tau imaging: early progress and future directions
Villemagne, V. L., Fodero-Tavoletti, M. T., Masters, C. L., & Rowe, C. C. (2015) · The Lancet Neurology · doi:10.1016/s1474-4422(14)70252-2 · Cited by 501 · see citing works
Alzheimer disease therapy—moving from amyloid-β to tau
Giacobini, E., & Gold, G. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2013.223 · Cited by 483 · see citing works
Agdeppa, E. D., Kepe, V., Liu, J., Flores-Torres, S., Satyamurthy, N., Petrič, A., Cole, G. M., Small, G. W., Huang, S., & Barrio, J. R. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-24-j0004.2001 · Cited by 421 · see citing works
Harada, R., Okamura, N., Furumoto, S., Furukawa, K., Ishiki, A., Tomita, N., Tago, T., Hiraoka, K., Watanuki, S., Shidahara, M., et al. (2016) · Journal of Nuclear Medicine · doi:10.2967/jnumed.115.164848 · Cited by 330 · see citing works
18F-THK523: a novel in vivo tau imaging ligand for Alzheimer's disease
Fodero‐Tavoletti, M. T., Okamura, N., Furumoto, S., Mulligan, R. S., Connor, A. R., McLean, C., Cao, D., Rigopoulos, A., Cartwright, G. A., O'Keefe, G. J., et al. (2011) · Brain · doi:10.1093/brain/awr038 · Cited by 329 · see citing works
Ligand-Binding Affinity Estimates Supported by Quantum-Mechanical Methods
Ryde, U., & Söderhjelm, P. (2016) · Chemical Reviews · doi:10.1021/acs.chemrev.5b00630 · Cited by 301 · see citing works
Okamura, N., Furumoto, S., Harada, R., Tago, T., Yoshikawa, T., Fodero‐Tavoletti, M. T., Mulligan, R. S., Villemagne, V. L., Akatsu, H., Yamamoto, T., et al. (2013) · Journal of Nuclear Medicine · doi:10.2967/jnumed.112.117341 · Cited by 289 · see citing works
Tau PET imaging: present and future directions
Saint‐Aubert, L., Lemoine, L., Chiotis, K., Leuzy, A., Rodriguez‐Vieitez, E., & Nordberg, A. K. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0162-3 · Cited by 283 · see citing works
Self-citationHostetler, E. D., Walji, A. M., Zeng, Z., Miller, P. J., Bennacef, I., Salinas, C. A., Connolly, B., Gantert, L. T., Haley, H., Holahan, M. A., et al. (2016) · Journal of Nuclear Medicine · doi:10.2967/jnumed.115.171678 · Cited by 275 · see citing works
Levy, R. M., Karplus, M., Kushick, J. N., & Pérahia, D. (1984) · Macromolecules · doi:10.1021/ma00137a013 · Cited by 248 · see citing works
Fragment Quantum Mechanical Calculation of Proteins and Its Applications
He, X. D., Zhu, T., Wang, X., Liu, J., & Zhang, J. Z. H. (2014) · Accounts of Chemical Research · doi:10.1021/ar500077t · Cited by 209 · see citing works
Ono, M., Sahara, N., Kumata, K., Ji, B., Ni, R., Koga, S., Dickson, D. W., Trojanowski, J. Q., Lee, V. M. ‐., Yoshida, M., et al. (2016) · Brain · doi:10.1093/brain/aww339 · Cited by 202 · see citing works
Self-citationWalji, A. M., Hostetler, E. D., Selnick, H. G., Zeng, Z., Miller, P. J., Bennacef, I., Salinas, C. A., Connolly, B., Gantert, L. T., Holahan, M. A., et al. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00166 · Cited by 181 · see citing works
Binding Modes of Thioflavin-T to the Single-Layer β-Sheet of the Peptide Self-Assembly Mimics
Wu, C. F., Biancalana, M., Koide, S., & Shea, J. (2009) · Journal of Molecular Biology · doi:10.1016/j.jmb.2009.09.056 · Cited by 138 · see citing works
Interaction of the amyloid imaging tracer FDDNP with hallmark Alzheimer’s disease pathologies
Thompson, P. W., Ye, L., Morgenstern, J. L., Sue, L. I., Beach, T. G., Judd, D. J., Shipley, N. J., Libri, V., & Lockhart, A. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.05996.x · Cited by 133 · see citing works
Tau imaging in neurodegenerative diseases
Dani, M., Brooks, D. J., & Edison, P. (2015) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-015-3231-2 · Cited by 125 · see citing works
A High Affinity Red Fluorescence and Colorimetric Probe for Amyloid β Aggregates
Rajasekhar, K., Narayanaswamy, N., Murugan, N. A., Kuang, G., Ågren, H., & Govindaraju, T. (2016) · Scientific Reports · doi:10.1038/srep23668 · Cited by 111 · see citing works
Self-citationLemoine, L., Gillberg, P.-G., Svedberg, M. M., Stepanov, V. A., Jia, Z., Huang, J., Nag, S., Tian, H., Ghetti, B. F., Okamura, N., et al. (2017) · Alzheimer s Research & Therapy · doi:10.1186/s13195-017-0325-z · Cited by 108 · see citing works
Self-citationArima, K. (2006) · Neuropathology · doi:10.1111/j.1440-1789.2006.00669.x · Cited by 106 · see citing works
Multitracer PET imaging of amyloid plaques and neurofibrillary tangles in Alzheimer's disease
Shin, J., Lee, S., Kim, S., Kim, Y.-B., & Cho, S. (2008) · NeuroImage · doi:10.1016/j.neuroimage.2008.07.022 · Cited by 101 · see citing works
In vivo tau imaging: Obstacles and progress
Villemagne, V. L., & Okamura, N. (2014) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2014.04.013 · Cited by 96 · see citing works
Jiang, P., Li, W., Shea, J., & Mu, Y. (2011) · Biophysical Journal · doi:10.1016/j.bpj.2011.02.010 · Cited by 84 · see citing works
Visualization of regional tau deposits using 3H-THK5117 in Alzheimer brain tissue
Lemoine, L., Saint‐Aubert, L., Marutle, A., Antoni, G., Eriksson, J., Ghetti, B. F., Okamura, N., Nennesmo, I., Gillberg, P.-G., & Nordberg, A. K. (2015) · Acta Neuropathologica Communications · doi:10.1186/s40478-015-0220-4 · Cited by 65 · see citing works
Self-citationComparison of New Tau PET-Tracer Candidates With [ 18 F]T808 and [ 18 F]T807
Declercq, L., Celen, S., Lecina, J., Ahamed, M., Tousseyn, T., Moechars, D., Alcázar, J., Ariza, M., Fierens, K., Bottelbergs, A., et al. (2016) · Molecular Imaging · doi:10.1177/1536012115624920 · Cited by 61 · see citing works
Söderhjelm, P., Aquilante, F., & Ryde, U. (2009) · The Journal of Physical Chemistry B · doi:10.1021/jp810551h · Cited by 56 · see citing works
Kuang, G.-L., Murugan, N., Tu, Y.-Q., Nordberg, A., & Ågren, H. (2015) · Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.5b05964 · Cited by 49 · see citing works
Self-citationThe Culprit Is in the Cave: The Core Sites Explain the Binding Profiles of Amyloid-Specific Tracers
Murugan, N. A., Halldin, C., Nordberg, A. K., Långström, B., & Ågren, H. (2016) · The Journal of Physical Chemistry Letters · doi:10.1021/acs.jpclett.6b01586 · Cited by 40 · see citing works
Self-citationLiu, J., He, X. D., & Zhang, J. Z. H. (2013) · Journal of Chemical Information and Modeling · doi:10.1021/ci400067c · Cited by 39 · see citing works
Amyloid Fibril-Induced Structural and Spectral Modifications in the Thioflavin-T Optical Probe
Murugan, N. A., Olsen, J. M. H., Kongsted, J., Rinkevičius, Ž., Aidas, K., & Ågren, H. (2012) · The Journal of Physical Chemistry Letters · doi:10.1021/jz3018557 · Cited by 31 · see citing works
Self-citationCai, L., Qu, B., Hurtle, B. T., Dadiboyena, S., Diaz-Arrastia, R. R., & Pike, V. W. (2016) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.6b00051 · Cited by 30 · see citing works
Vermeiren, C., Mercier, J., Viot, D., Mairet‐Coello, G., Hannestad, J. O., Courade, J., Citron, M., & Gillard, M. R. (2015) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2015.07.381 · Cited by 30 · see citing works
Wang, J., Zhou, X., Liu, S., et al. (2015) · Scientific Reports · doi:10.1038/srep08864 · Cited by 25 · see citing works
Integrative approaches in HIV ‐1 non‐nucleoside reverse transcriptase inhibitor design
Poongavanam, V., Namasivayam, V., Vanangamudi, M., Shamaileh, H. A., Veedu, R. N., Kihlberg, J. O., & Murugan, N. A. (2017) · Wiley Interdisciplinary Reviews Computational Molecular Science · doi:10.1002/wcms.1328 · Cited by 21 · see citing works
Self-citationLi, J., Liu, W. C., Luo, H., et al. (2016) · Journal of Molecular Modeling · doi:10.1007/s00894-016-3099-5 · Cited by 11 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
van Oostveen, W. M., & de Lange, E. C. M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22042110 · Cited by 297 · see citing works
Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models
Silva, M. C., Ferguson, F. M., Cai, Q., Donovan, K. A., Nandi, G., Patnaik, D., Zhang, T., Huang, H.-T., Lucente, D. E., Dickerson, B. C., et al. (2019) · eLife · doi:10.7554/elife.45457 · Cited by 283 · see citing works
Artificial Intelligence and the Future of Diagnostic and Therapeutic Radiopharmaceutical Development
Ataeinia, B., & Heidari, P. (2021) · PET Clinics · doi:10.1016/j.cpet.2021.06.008 · Cited by 31 · see citing works
- Authors
- Murugan, N. A., Nordberg, A., & Ågren, H.
- Affiliations
- AlbaNova (SE)
- Karolinska University Hospital (SE)
- Uppsala University (SE)
- Corresponding author
- Murugan, N. Arul
- Venue
- ACS Chemical Neuroscience
- Publisher
- American Chemical Society (ACS)
- Published
- 2018-04-09
- Volume
- 9
- Issue
- 7
- Pages
- 1757-1767
- ISSN
- 1948-7193 (ISSN-L)
- OpenAlex
- W2797441036
- Cited by
- 92
- References
- 52
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 9 · 2023: 18 · 2022: 14 · 2021: 16 · 2020: 14 · 2019: 3 · 2018: 3
- FWCI
- 6.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- ACS Chemical Neuroscience (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Funders
- Stiftelsen f??r??Strategisk Forskning (RB13-0192)
- Kungliga Tekniska H??gskolan (NA)
- Stockholms L??ns Landsting (NA)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- binding sites, Alzheimer's disease, cryo-EM structure, binding affinity, off-target binding, amyloid-beta, molecular docking, binding free energy
- MeSH terms
- Animals, Binding Sites, Humans, Amyloid beta-Peptides, tau Proteins, Protein Structure, Secondary, Radiopharmaceuticals, Positron-Emission Tomography, Protein Multimerization, Molecular Dynamics Simulation, Molecular Docking Simulation, Protein Aggregation, Pathological
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review