Download De novo structure-based ligand design software

De novo structure-based ligand design software
OVERVIEW
Keymodule Ltd.
SPROUT is an effective tool for the design of drug-like, biologically active molecules. It is an
interactive system that can assist in several stages of the structure-based rational drug design
process.
The system is modularised and offers automatic methods for solving a number of problems in
drug design. The user maintains control and is able to guide the operation of each module for
maximum versatility.
FUNCTIONS
• Binding pocket identification in the solvent accessible surface of the protein complex
• Identification of favourable hydrogen bonding, metal bonding and hydrophobic regions or
specification of user generated target sites within the binding pocket
• Docking of small fragments to target sites to form starting points for structure generation;
alternatively importing of larger fragments (and if necessary structure modification e.g. deletion
of a central core to allow replacement – scaffold hopping). Key step in “fragment based drug
design” using NMR or crystallographically derived fragments.
• Fragment joining to build skeletons from the starting groups and/or imported fragments by
incremental construction always satisfying the steric constraints of the binding pocket
• Scoring and sorting the solutions on estimated binding affinity and synthetic feasibility
VALIDATION
Our validation experiments show that SPROUT is able to regenerate structures of known drugs,
and due to its exhaustive exploration of the search space it routinely suggests novel solutions
with higher predicted binding affinity than the known inhibitors.
RECENT SUCCESS STORIES
• G.E. Besong, J.M. Bostock, W. Stubbings, I. Chopra, A.P. Johnson, D.I.Roper, A.J. Lloyd, and
C.W.G. Fishwick. A novel de novo designed inhibitor of D-ala-D-ala ligase from E.coli.
Angew. Chem. Int. Ed. Engl., 2005, 44, 6403 – 6.
• T.Heikkila, S. Thirumalairagan, M. Davies, A.P. Johnson, G. McConkey, and C.W.G Fishwick.
The first de novo designed inhibitors of plasmodium falciparum dihydroorotate
dehydrogenase. Bioorg. Med. Chem. Lett., 2006, 16, 88-92.
• Structure-based design of inhibitors of class 2 dihydroorotate dehydrogenases (T.J. Heikkilä,
M. Davies, M.R. Parsons, A.P. Johnson) *
• Design and Synthesis of New Dihydroorotate Dehydrogenase Inhibitors as Potent
Antimalarials (Davies M., Heikkilä T.J., Fishwick C.W.G., and A.P Johnson) *
* see attached posters
De novo structure-based ligand design software
Keymodule Ltd.
A protein of p38 MAP kinase is selected to illustrate SPROUT’s ability to design novel ligands
with high predicted binding affinity.
SPROUT generates 5919 structures
many of which have a higher binding
affinity than -10. The best scored
structure has a value of -13.67 (see
chart).
2500
Number of structures
The crystal structure of p38 MAP
kinase complex with Inhibitor1 is an
entry of the Protein Data Bank (PDB
code: 1KV1). Inhibitor1 has a binding
affinity of -10.17 estimated by
SPROUT.
2000
1500
1000
500
0
-14 to -13
-13 to -12
-12 to -11
-11 to -10
-10 to -9
-9 to -8
-8 to -7
Estimated binding affinity
Score: -13.12
Structures coloured blue:
Two hits after heteroatom
substitution having highest
predicted binding affinity.
Structure coloured gold:
Inhibitor1
Score: -12.82