MOE has a unified framework for
fragment-based and de novo design applications which can be applied to
both ligand- and structure-based design projects. MOE's pharmacophore
applications are integrated into the fragment based design protocol which
provides an effective methodology for generating novel structures while
preserving key interactions.
- Grow, link, transform and replace ligand scaffolds
(with or without the receptor)
- Refine coordinates in a (flexible) active site and calculate binding scores
- Apply MOE pharmacophore filters for preserving interactions or functional groups
- Automatically apply 2D and 3D descriptors, QSAR and fingerprint constraints
- Search MOE .mdb or Omega .oeb files directly and create in-house fragment databases
[Grimshaw 2010] for fast follow-on compounds by incorporating
innovative linear, cyclic or fused scaffold arrangements. Select multiple
exit vectors and perform simultaneous searches to generate diversity
oriented scaffolds. Exchange ring bonds to identify and incorporate fused
ring arrangements. Specify optional connection vectors to increase
the scope of scaffold arrangements and allow for cyclization at multiple
Combine fragments of bound ligands (crystal
structures or docking poses) to create novel structures in the context
of a receptor active site [Pierce 2004]. Ligand fragments are
exchanged between all pairs of ligands along all overlaid "crossover¡±
bonds. Crossover bonds may be restricted to bias the generated structures
towards synthetic accessibility.
or elaborate on a key fragment at one or more positions in the context of an active
site. Link fragments to connect two or more independent fragments.
Specify optional or essential connection points for increased flexibility.
Perform small isosteric changes to a
molecule by applying reaction transformations rules (.rxn) that are generated
using standard 2D sketchers. CCG provides a database of 170+
medicinal chemistry transformations. Custom transformations can be easily
added to the database and multiple iterations can be automatically applied for
building combinatorial combinations or evolving transformations over multiple
generations to produce more complex fragment and bioisosteres.
Filter the generated structures using any
of MOE's hundreds of descriptors. Apply SMARTS pattern
matches to include or exclude substructures present in molecules. Apply
QSAR, fingerprint or pharmacophore models as additional filters.
Use shape based pharmacophore queries for ligand based design
projects. Estimate the "synthetic feasibility" using the MOE
rsynth descriptor. Refine structures in a (flexible) pocket and
apply scoring functions to estimate binding affinity.
Create in-house fragment databases
using MOE's SD Pipeline Tools. Enumerate protonation states and
filter input SD files to obtain good starting structures for
fragmentation. Keep only structures that are leadlike, non-reactive, etc.
Fragment molecules using a combination of algorithms and generate
conformations. Use commercial or customized in-house reagents
as input to a reaction engine to generate R-group or scaffold libraries.
[Clark 2008] Clark, A.M., Labute, P.;SD
File Processing with MOE Pipeline Tools.; JCCG (2008)
[Deschenes 2007] Deschenes, A., Sourial, E.;Ligand
Scaffold Replacement using MOE Pharmacophore Tools.; JCCG (2007)
[Pierce 2004] Pierce, A.C., Rao, G.,
Bemis, G.W.; BREED: Generating Novel Inhibitors through Hybridization of Known
Ligands. Application to CDK2, P38 and HIV Protease; J. Med. Chem. 47 (2004)
[Grimshaw 2010] Grimshaw, S.; Scaffold Replacement in MOE; JCCG (2010)