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AceDock: Virtual Screening And Docking

Screening large compound libraries

Screening

Screening allows for reducing the compounds which need to go to experimental testing. Our docking protocol, where we used KDEEP to re-score docked poses, won 2 blind sub-challenges of the D3R Grand Challenge 4. With our docking software, we can cover several relevant scenarios:

  • Free docking: No restrictions or prior knowledge is imposed in the docking exercise. Poses are re-scored with KDEEP.
  • Scaffold-hopping: Identify compounds in your library with great pharmacophoric overlap against a known binder.
  • Ensemble docking: We build an ensemble of conformations for your pocket to model protein flexibility.
  • Template docking: Use a known binder to guide the docking of a similar compound or series.
  • Constrained docking: Impose restrictions so certain moieties in the ligand (e.g. aromatic rings) are placed in the right spot.

Steps

  1. Protein preparation: The most suitable protonation states will be determined and hydrogens will be added.
  2. Mixed solvent molecular dynamics: The protonated target is simulated in a mixture of water and a fragment-size molecule, like benzene.
  3. Pocket profiling: Pharmacophores, structural waters and pocket ensembles are obtained from the simulations.
  4. Homolog search: Exhaustive search among public databases to find similar homologs with bound small molecules to further refine the pharmacophore.
  5. Molecular docking: The library of choice will be docked against the pocket ensemble and the obtained poses will be rescored after taking the pharmacophore and the waters into account.
  6. Ranking: The best compounds will be inspected and a short list of the most promising ones will be provided.

Results

  • A PlayMolecule scene with binding mode predictions for the most promising compounds.
  • A ranking of compounds.
  • An extensive report summarizing the structural insights obtained.

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