Docking for Molecules That Bind in a Symmetric Stack with SymDOCK.

Area of Science:

• Biochemistry
• Computational Chemistry
• Structural Biology

Background:

• Amyloid fibrils, particularly tau protein aggregates, are implicated in neurodegenerative diseases.
• Ligand binding to these fibrils often exhibits symmetry and stacking, interacting primarily with each other rather than the protein.

Purpose of the Study:

• To develop a computational method, SymDOCK, that exploits the symmetry and stacking of ligands within amyloid fibrils.
• To improve the accuracy and efficiency of identifying potential drug candidates for tauopathies.

Main Methods:

• SymDOCK applies symmetry operations to generate self-interacting ligand stacks, assessing steric clashes and ligand-ligand interactions.
• Docking scores are enhanced by van der Waals energy, with quantum mechanical validation using ANI.
• The method was tested retrospectively on known tau PET tracers and prospectively on MK-6240.

Main Results:

• SymDOCK successfully reproduced known binding poses of tau PET tracers.
• It prospectively predicted the binding structure of MK-6240 in AD PHF tau fibrils before experimental determination.
• The method demonstrated enrichment of known ligands over decoys in screens without compromising speed.

Conclusions:

• SymDOCK is an effective tool for identifying symmetrical stackers within amyloid fibrils.
• This approach accelerates the discovery of ligands targeting tau protein, with potential applications in large-scale drug screening for neurodegenerative diseases.