Cryo-EM structure of Alzheimer’s disease tau filaments with PET ligand MK-6240

Kunach, Peter; Vaquer-Alicea, Jaime; Smith, Matthew S.; Hopewell, Robert; Monistrol, Jim; Moquin, Luc; Therriault, Joseph; Tissot, Cecile; Rahmouni, Nesrine; Massarweh, Gassan; Soucy, Jean-Paul; Guiot, Marie-Christine; Shoichet, Brian K.; Rosa-Neto, Pedro; Diamond, Marc I.; Shahmoradian, Sarah H.

doi:10.1101/2023.09.22.558671

Cited by 12 publications

(15 citation statements)

References 49 publications

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“…Indeed, the structure was close enough that the docked pose was used as the input for refinement of the final experimental structure of the MK-6240/AD PHF tau complex. 56 We note that although this was the 9th-best scoring structure, the best pose by DOCK score ha an RMSD of 3.01 Å from the experimental structure, and the third-best scoring pose had an RMSD of 2.27 Å to the experimental structure.…”

Section: Docking 22 Millionmentioning

confidence: 83%

“…4), and that docking pose was in fact used in the solution of the ligand-complex structure as determined by cryo-EM. 56 Several limitations of SymDOCK merit airing. For speed of calculation, we have used a 2 Å cutoff to define ligand-ligand clashes, which misses those owing to large radii atoms like bromine or iodine.…”

Section: Discussionmentioning

confidence: 99%

“…4 ), and that docking pose was in fact used in the solution of the ligand-complex structure as determined by cryo-EM. 56…”

Section: Discussionmentioning

confidence: 99%

“…PK ran the experiments and computational analysis to provide the electron density and protein model for the structure of MK-6240 bound to AD PHF tau, under the supervision of MID and SHS, as described in an accompanying manuscript. 56 All authors contributed to writing and editing the paper.…”

Section: Author Contributionsmentioning

confidence: 99%

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Docking for molecules that bind in a symmetric stack with SymDOCK

Smith,

Knight,

Kormos

et al. 2023

Preprint

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Discovering ligands for amyloid fibrils, such as those formed by the tau protein, is an area of much current interest. In recent structures, ligands bind in stacks in the tau fibrils to reflect the rotational and translational symmetry of the fibril itself; in these structures the ligands make few interactions with the protein but interact extensively with each other. To exploit this symmetry and stacking, we developed SymDOCK, a method to dock molecules that follow the protein’s symmetry. For each prospective ligand pose, we apply the symmetry operation of the fibril to generate a self-interacting and fibril-interacting stack, checking that doing so will not cause a clash between the original molecule and its image. Absent a clash, we retain that pose and add the ligand-ligand van der Waals energy to the ligand’s docking score (here using DOCK3.8). We can check these geometries and energies using an implementation of ANI, a neural network-based quantum-mechanical evaluation of the ligand stacking energies. In retrospective calculations, symmetry docking can reproduce the poses of three tau PET tracers whose structures have been determined. More convincingly, in aprospectivestudy SymDOCK predicted the structure of the PET tracer MK-6240 bound in a symmetrical stack to AD PHF tau before that structure was determined; the docked pose was used to determine how MK-6240 fit the cryo-EM density. In proof-of-concept studies, SymDOCK enriched known ligands over property-matched decoys in retrospective screens without sacrificing docking speed, and can address large library screens that seek new symmetrical stackers. Future applications of this approach will be considered.

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Section: Docking 22 Millionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

“…4 ), and that docking pose was in fact used in the solution of the ligand-complex structure as determined by cryo-EM. 56…”

Section: Discussionmentioning

confidence: 99%

Section: Author Contributionsmentioning

confidence: 99%

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Docking for molecules that bind in a symmetric stack with SymDOCK

Smith,

Knight,

Kormos

et al. 2023

Preprint

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“…The new ligands’ poses seem plausible, forming stacks around planar aromatic and heteroaromatic systems while preserving the symmetry of the fibril (Figure ). In a genuine prospective prediction, the method correctly predicts the binding pose of MK-6240 to AD PHF tau (Figure ), and that docking pose was in fact used in the solution of the ligand-complex structure as determined by cryo-EM …”

Section: Discussionmentioning

confidence: 99%

Docking for Molecules That Bind in a Symmetric Stack with SymDOCK

Smith,

Knight,

Kormos

et al. 2024

J. Chem. Inf. Model.

Self Cite

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Discovering ligands for amyloid fibrils, such as those formed by the tau protein, is an area of great current interest. In recent structures, ligands bind in stacks in the tau fibrils to reflect the rotational and translational symmetry of the fibril itself; in these structures, the ligands make few interactions with the protein but interact extensively with each other. To exploit this symmetry and stacking, we developed SymDOCK, a method to dock molecules that follow the protein's symmetry. For each prospective ligand pose, we apply the symmetry operation of the fibril to generate a self-interacting and fibril-interacting stack, checking that doing so will not cause a clash between the original molecule and its image. Absent a clash, we retain that pose and add the ligand−ligand van der Waals energy to the ligand's docking score (here using DOCK3.8). We can check these geometries and energies using an implementation of ANI, a neural-network-based quantum-mechanical evaluation of the ligand stacking energies. In retrospective calculations, symmetry docking can reproduce the poses of three tau PET tracers whose structures have been determined. More convincingly, in a prospective study, SymDOCK predicted the structure of the PET tracer MK-6240 bound in a symmetrical stack to AD PHF tau before that structure was determined; the docked pose was used to determine how MK-6240 fit the cryo-EM density. In proof-of-concept studies, SymDOCK enriched known ligands over property-matched decoys in retrospective screens without sacrificing docking speed and can address large library screens that seek new symmetrical stackers. Future applications of this approach will be considered.

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PROGRESS IN IDENTIFYING BINDERS TO DISEASE-RELEVANT TAU AND Α-Synuclein WITH THERAPEUTIC OR DIAGNOSTIC POTENTIAL

Capacci,

Paras

2024

Medicinal Chemistry Reviews

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Cryo-EM structure of Alzheimer’s disease tau filaments with PET ligand MK-6240

Cited by 12 publications

References 49 publications

Docking for molecules that bind in a symmetric stack with SymDOCK

Docking for molecules that bind in a symmetric stack with SymDOCK

Docking for Molecules That Bind in a Symmetric Stack with SymDOCK

PROGRESS IN IDENTIFYING BINDERS TO DISEASE-RELEVANT TAU AND Α-Synuclein WITH THERAPEUTIC OR DIAGNOSTIC POTENTIAL

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