Edit

Chemical Biology Core Facility

Small molecules play essential roles in many areas of basic research and are often used to address important biological questions.

Computational Chemistry

Computational chemistry methods are integral to the process of active molecule identification and optimisation. These include:

  • Chemoinformatics approaches
  • Molecular modelling
  • Computational screening using ligand-based and structure-based design strategies
  • Managing compound acquisition through our chemistry partners
  • Commercial software available: SYBYL-X including SurflexDock and SurflexSim, LeadIT including FlexX and FlexS, Muse, Spartan
  • Access to the HPC compute cluster at EMBL which provides access to more than 5800 CPUs for scientific computing at EMBL

Structural biology

  • Protein structure visualisation (3D visualisation capabilities)
  • Binding site identification
  • Analysis of interaction profiles of ligands inside a binding site
  • Homology modeling; leveraging known protein structures to unknowns with similar sequence

Ligand-based design

  • Pharmacophore elucidation based on known active ligands
  • Database searching for new active compounds based on pharmacophore
  • Properties prediction based on models from data of known ligands
  • SAR, ADME predictions based on data from known ligands
Three MAP-kinase P38 inhibitors were analyzed and important features for binding detected. These are two hydrophobic groups (cyan spheres in the right part of the picture) plus a hydrogen bond accepting capability (green). This is found in all three compounds. Having an additional hydrophobic feature (cyan sphere in the centre of the picture) and another hydrogen bond accepting group at the magenta spot enhance affinity as the green and the purple molecule sharing these features have higher inhibitor activity.
Three MAP-kinase P38 inhibitors were analyzed and important features for binding detected. These are two hydrophobic groups (cyan spheres in the right part of the picture) plus a hydrogen bond accepting capability (green). This is found in all three compounds. Having an additional hydrophobic feature (cyan sphere in the centre of the picture) and another hydrogen bond accepting group at the magenta spot enhance affinity as the green and the purple molecule sharing these features have higher inhibitor activity.

Receptor-based design

  • Docking of ligands into target structure
    • Virtual screening; selection of compounds from large data set based on docking
    • Ligand refinement based on docked structure
  • De novo design of ligands from protein structure; no lead compound; spatial arrangement of suitable binding groups
Docking of ligands

Data analysis

  • Diversity and similarity tools
  • Library creation
    • For random screening
    • For specific targets
    • Exploration of SAR (iterative)
Data analysis approaches

Library design

  • Diversity and similarity tools
  • Library creation
    • For random screening
    • For specific targets
    • Exploration of SAR (iterative)
The probability to detect active compounds will be higher with a compound library designed to be diverse.
Designing a focused compound library in order to learn about the structure-activity relationship and improve on molecular properties.

Compound acquisitions

  • Identifying vendors and availability of desired compounds
  • Quote requests

Edit