vilmos a. valko and a. peter johnson
TRANSCRIPT
PDB: 2vu3Score: -8.16
PDB: 2vtqScore: -8.32
PDB: 2vtpScore: -7.94
Structures very similar to med. chem. optimization end results were alsogenerated having slightly lower estimated scores in SPROUT-HitOpt
Vilmos A. Valko and A. Peter Johnson
School of ChemistryUniversity of Leeds
Leeds, LS2 9JT
Keymodule Ltd.
www.keymodule.co.uk
+44 113 343 6595
Readily synthesizableputative
ligand structures
Reliable highyielding
reactions
SyntheticKnowledge
Base Pool of readilyavailablestarting
materials
FragmentLibrary
fuse
spiro
newbond
SPROUT Built in / user definedreactions:• Amide formation• Ether formation• Ester formation• Amine alkylation• Reductive amination• etc.
SynSPROUT
Ease ofsynthesis
is a keyfactor
in drugdevelopment
Buildsyntheticconstraints
intostructure
generationprocess
VIRTUAL SYNTHESISIN
RECEPTOR CAVITY
SynSPROUT Scheme
List of reactions (betweenfunctional groups)
SyntheticKnowledge Base
Simulatesynthetic
reaction inthe 3D
context ofreceptor
site
R23
R13
CORER12
R22
R33R32R31
R11
R21Multiple low energyconformers +detected functional groups
Core Structure
Monomer Library General Scheme
S
NH2
ClOO
NH2
HO O
NH2
HN
ClOHO
HO
OH
O
All possible core +monomer combinations
are generated
S
OO
NH
HO
S
OO
NH
O
HN
HN
HN
OH
O
HN
O
CORE
HN
OH
O
CORE
S
OO
NH
HO
CORE
S
OO
NH
O
HN
HN
CORE
S
OO
NH
HO
CORE
S
OO
NH
O
HN
OCORE
SPROUT FamilySPROUT Sophisticated de novo design tool Design new hit compounds from scratch within the active site of your target Build structures using imported fragments – recore as standard feature Excellent synergy with fragment-based hit discovery Predicts binding affinity and synthetic feasibility (via complexity analysis) Proven record of success
SPROUT-HitOpt Optimize hit compounds with the target’s active site Synthetic constraints ensure only synthetically accessible structures are generated Two modes of optimization – Core Extension and Monomer Replacement
SynSPROUT Generate synthetically accessible ligands by virtual chemistry within protein cavity Use a library of readily available starting materials (monomers) Editable reaction knowledge base
SynSPROUT Approach
Core Extension in SPROUT-HitOpt Optimization of a CDK2 fragment based onindazole [1]
Synthetic Knowledge Base
CHEMICAL-LABEL <Carboxylic Acid>C[SPCENTRE=2](=O)-O[HS=1]CHEMICAL-LABEL <Primary Amine>C-N[HS=2];[CONNECTION=1]
Steps of formation Hybridization changes Bond type Bond length Dihedral penalty/angle
Steps of Joining Rules
RULE Amide FormationIF Carboxylic Acid INTER Primary AmineTHEN delete-atom 3
change-hybridization 5 to SP2form-bond - between 1 and 5
DIHEDRAL-ATOMS 2 1 5 4DIHEDRAL 0 0BOND-LENGTH 1.35END-THEN
O
OH
H2N
HN
O
+1
2
3
4
5
Identification of reactive functional groups as possible extension points Adding monomers from a user-defined monomer library at the extension pointsvia synthetic reactions Scoring the binding affinity of each core + monomer product to automaticallyselect the best scored conformations
Monomer Replacement in SPROUT-HitOpt Identification of monomers through retrosynthetic analysis Replacing the monomers by similar ones taken from a user-defined monomerlibrary, making use of a pre-built structure-based hierarchy of the monomers toimprove efficiency Scoring the binding affinity of the modified structures
O
NH
N
OH
O
OH
N
OH
H2N
Br
H2N
Br
Cl
O
NH
N
OH
ClClStarting Structural Motif
Retrosynthetic Analysis
Monomers
Replace monomeric units bysuperstructure fragments,
redock and rescore
Findsuperstructuresof monomers
in hierarchy
Superstructures
[1]: P. G. Wyatt et al. J. Med. Chem. 2008, 51, 16.
NH
N
MW = 118IC50 = 185 μMLE = 0.57
Asp145Asp86
Leu134
Leu83
Phe82Glu81
Phe80
Lys33
Core StructureOriginal Hit
Manuallyintroducefunctional
groups
Primaryamine
Carboxylicacid
N NOH
ONH2
Monomer Library
Generated from Maybridge andSigma Aldrich compounddatabases
8334Carboxylic Acids
6773Primary Amines
4674Secondary Amines
Core Extension withrestriction onmovementof pyrazole
3648 combinationswere generated
Binding affinity score: -8.53 Binding affinity score: -8.61
Two results with high binding affinity score and LE after Core Extension
(HO)2B (HO)2B
Cl
MonomerReplacement
49,544structures were
generated
Two results with high binding affinity score and LE after Monomer Replacement
Starting Structural Motif
Optimization of a CDK2 fragment based onpyrazole [1]
Score: -8.53LE: 0.29
Score: -8.28LE: 0.26
Score: -8.80LE: 0.31
Score: -8.77LE: 0.29
Amide FormationReductive AminationSulphonamide Formation
SyntheticKnowledge Base
NH
N
NH NH
O
O
HN N
NHO
NH
F
O
F F
HN N
NHO
NH
O
F F
NH
HN N
NHO
NH
O
Cl Cl
NH