Pharmacophore Discovery

MOE contains the industry-leading suite of pharmacophore discovery applications used for fragment-, ligand- and structure-based design projects.  Pharmacophore modeling is a powerful means to generate and use 3D information to search for novel active compounds, particularly when no receptor geometry is available.  Pharmacophore methods use a generalized molecular recognition representation and geometric constraints to bypass the structural or chemical class bias of 2D methods.

Construct queries with an easy-to-use interactive query editor using either proteins or ligands.  Use the query to screen a conformational database to determine candidate active compounds that satisfy the pharmacophore model.  Customize pharmacophore annotations with SMARTS chemical patterns and Boolean expressions.  Restrict shape (receptor or ligand) with volume constraints and refine the query with directional vector constraints, centroids of atoms, or partial matches on annotations.  Apply MOE’s active site analysis tools help identify key interactions of molecular recognition.

Elucidate pharmacophore queries and induced molecular alignments from a collection of input compounds (possibly with activity data) by considering all possible discrete geometries and all possible combinations of feature query expressions.  Enforce limits on feature counts and add custom query expressions.  Score queries based on known active compound coverage, statistical activity enrichment and atomic overlap of matching conformations.  Protein Ligand Interaction Fingerprints (PLIF) can automatically generate queries from bound ligands given a set of aligned complexes (or docking results). 

Construct 3D conformation databases for virtual screening from SD files or SMILES strings using MOE's parallelized High Throughput Conformational Search application.  Prepare compound collections with sdtools for duplicate removal, tautomer and ionization state and stereo enumeration, fragment generation, and property filtering.  CCG provides a large lead-like whole molecule 3D database and a large fragment database derived from vendor catalogs and medicinal chemistry literature.

Rapidly screen a conformational database for compound conformations that satisfy a pharmacophore query.  Search multiple databases, a sub-range of molecules or a database of docked compounds. Search MOE MDB, or Omega OEB files directly.  Output data consists of molecules that satisfy the 3D pharmacophore query (either all conformations or just the conformations that satisfy the query).  Partial matches, SMARTS patterns, output of all symmetric matches and specification of essential features are supported.  Screen corporate collections in minutes on a compute cluster.

Grow, link, and replace [Grimshaw 2010] ligand scaffolds (with or without the receptor).  Medicinal chemistry transformations perform small isosteric changes to a molecule rely on reaction transformations (.rxn) that are generated using standard sketchers.  CCG provides a database of 170+ transformations.  Refine coordinates in the active site if available (flexible receptor) and calculate binding scores while retaining pharmacophore features.  Apply 2D and 3D descriptor filters, QSAR and fingerprint models. 

[Deschenes 2007] Deschenes, A., Sourial, E.; Ligand Scaffold Replacement using MOE Pharmacophore Tools.; JCCG (2007)

[Grimshaw 2010] Grimshaw, S.; Scaffold Replacement in MOE; JCCG (2010)

[Labute 2001] Labute, P., Williams, C., Feher, M., Sourial, E., Schmidt, J. M.; Flexible Alignment of Small Molecules; J. Med. Chem. 44 (2001) 1483–1490.