CSD-CrossMiner

CSD-CrossMiner is an interactive and highly versatile pharmacophore query tool that allows users to identify patterns and ideas for lead optimisation and scaffold hopping.

CSD-CrossMiner allows crystal structure databases such as the Cambridge Structural Database (CSD) and the Protein Data Bank (PDB) to be simultaneously searched in terms of pharmacophore queries.

The user can select standard pharmacophore features including one-point definitions (heavy atom, hydrophobic, water, ...) or directional two-point definitions (planar ring, donor, exit vector, ...) but also:

• Create user-defined pharmacophore features
• Use relative constrains between features (inter- or intra-molecular)
• Specify if a feature is from a protein or small molecule
• Generate feature databases from in-house structural data
• Exclude regions in space
• Search for spatial orientations of protein residues 

Search results are rapidly generated and overlaid onto the pharmacophore query, which can be refined at any time during the query. This delivers an overall interactive search experience with application areas in interaction searching, scaffold hopping or the identification of novel fragments for specific protein environments. For example use cases please see:
Korb O, Kuhn B, Hert J, Taylor N, Cole J, Groom C & Stahl M “Interactive and Versatile Navigation of Structural Databases” J Med Chem, 2016, 59(9):4257, DOI: 10.1021/acs.jmedchem.5b01756

CSD-Crossminer is the result of a close collaboration between CCDC and the Computer-Aided Drug Design Section of F. Hoffmann-La Roche Ltd at Roche Innovation Center Basel. CSD-CrossMiner is available within the CSD-Discovery and CSD-Enterprise suites.

Protein-ligand derived pharmacophore using 2HZI where pharmacophoric features belong to either Protein (P) or Small Molecule (S). These can be changed to find equivalent interactions in the CSD.

Download this video (3m04s)

Scaffold Hopping

Scaffold hopping allows you to identify novel scaffolds while keeping the key features of a compound, in order to improve its performance or avoid patented structures.

Scaffold hopping using reference ligand taken from the ABL kinase complex structure 2hzi

• Pharmacophore features are coloured as green (planar_ring_projected), red (hydrogen bond acceptor_projected), and white (exit_vector)
• The CSD is searched for matching hits which are instantly overlayed on the pharmacophore
• The hits are browsed using the 2D visualisation on the right, and shown overlaid in 3D with the pharmacophore

Download this video (2m42s)

An intermolecular hydrogen bonding pharmacophore query using structural information from the CSD

• Directional hydrogen bond donor (blue) acceptor (red) pair motif has been defined
• The ultrafast search returns results which are overlaid with the original query
• These results are browsed individually using the 2D hit list on the right of the screen

Download this video (1m38s)