fragment-based de novo design · fragment-based design • combinatorial optimization principle •...
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(c) G. Schneider @ EuroMug 4/11/04, Cambridge, UK
Fragment-based de novo Design
Gisbert Schneider & Uli Fechner
gisbert.schneider@modlab.dewww.modlab.de
Beilstein Endowed Chair for CheminformaticsInstitute of Organic Chemistry & Chemical BiologyJohann Wolfgang Goethe-UniversityFrankfurt, Germany
(c) G. Schneider @ EuroMug 4/11/04, Cambridge, UK
Navigation Is Defined As ...
"The process of determining and maintaining acourse or trajectory to a goal location“.(Franz & Mallot, Robot. Autonom. Syst. 2000, 30, 133)
(c) G. Schneider @ EuroMug 4/11/04, Cambridge, UK
• Coordinate system (“chemical space”)
• Guide through chemical space (“compass”, “map”)
• Target (“goal location”)
• Molecule generator (“vessel”)
What We Need for Exploration
Each map has a certain resolution & meaningEach map has a certain resolution & meaning
(c) G. Schneider @ EuroMug 4/11/04, Cambridge, UK
LibraryDiversity
SAR Information M.C. Escher’s “Regular Division of the Plane I” © 1999 Cordon Art B.V. - Baarn - Holland. All rights reserved.F
O
N NH
N
O
O
NN
NOO
Scaffold-Hopping
De novo Design:Exploiting the “Twilight Zone”
(c) G. Schneider @ EuroMug 4/11/04, Cambridge, UK
Fragment-based Design
• combinatorial optimization principle• manageable size of search space• might result in chemically feasible molecular designs• “side-chains” and “scaffolds” are interchangeable
N NHN
N
Cl
N
NR1
R2
N
NR1
R2
Traditional “combinatorial thinking”Scaffolds & side-chains
Fragment-based designOnly “building-blocks” (fragments)
(c) G. Schneider @ EuroMug 4/11/04, Cambridge, UK
The Concept
RECAPDrug DB Fragment DB
• Reference Molecule(s)• Fitness Functions• Reference Molecule(s)• Fitness FunctionsReactions
Assemble(TOPAS: “Flux-Generator”)
Designed MoleculesDesigned Molecules
RECAP: Lewell et al. (1998) J. Chem. Inf. Comput. Sci. 38:511TOPAS: Schneider et al. (2000) J. Comp. Aided Mol. Des. 14:487
(c) G. Schneider @ EuroMug 4/11/04, Cambridge, UK
RECAP – Eleven Bond Cleavage Types
N N
O
N
O
O
O
N
Amide Ester Amine Urea
N
N
NN+O
Ether Olefin Quarternary N Arom. N aliph. C
N
O
N S
O
O
Lactam N aliph. C Arom. C arom. C SulphonamideLewell et al., JCICS 1998.
(c) G. Schneider @ EuroMug 4/11/04, Cambridge, UK
RECAP Applied to the COBRA DatabaseCOBRA: Schneider & Schneider (2003) QSAR Comb. Sci. 22:713
368646Sulphonamide
6131194Arom. C – Arom. C
170274Lactam N – Aliph. C
6011018Arom. N – Aliph. C
1648Quart. Nitrogen
00Olefin
76128Ether
68Urea
178489Amine
472978Ester
19044324Amide
Unique FragmentsTotal FragmentsReaction
(c) G. Schneider @ EuroMug 4/11/04, Cambridge, UK
TOPAS II: The Implementation
Select best solution
Stop?Yes No
3,788Reactions
Fragments
Generate λmolecules(mutation)
11Generate λ
diversemolecules
Start
Determine Quality(Daylight Fingerprints &Tanimoto Coefficient)
#Atoms (!H): 12-60#O+#N ≤ 12
End
(c) G. Schneider @ EuroMug 4/11/04, Cambridge, UK
Daylight Toolkit Functions
dt_fp_allocfp allocate a new fingerprintdt_fp_euclid compute the euclidean distance between two fingerprintsdt_fp_tanimoto compute the tanimoto coefficient of two fingerprints
dt_smirkin interpret a string as a generic reactiondt_utransform apply a reaction transform to an objectdt_umatch match a pattern against an object
dt_smartin interpret a SMARTS stringdt_cansmiles retrieve the canonical SMILES string of an objectdt_copy make a copy of an objectdt_dealloc remove an object from the systemdt_smilin interpret a SMILES stringdt_weight return the atomic weight of an atomdt_getrole get the role an object plays in a reactiondt_stream allocate a stream objectdt_next retrieve the next object in a compound object
(c) G. Schneider @ EuroMug 4/11/04, Cambridge, UK
SMIRKS/ ReactionSMILES for Virtual Synthesis
Aromatic-C + Aromatic-C
([c;R1:1][10*]).([10*][c;R1:2])>>[c;R1:1]-[c;R1:2]([c;R1:1][10*]).([10*][c;R1:2])>>[c;R1:1]-[c;R1:2]
Reaction type & site indexAromaticcarbon Member of
exactly one ring
Atom mapping index
+[10*][10*]
(c) G. Schneider @ EuroMug 4/11/04, Cambridge, UK
The TOPAS II “Flux-Generator”
NHN
F
F
O
HN
OHN
F
F
O
HN
F
HN
O
Parent Structure Child Structure
Step 1 Step 3
N
O
Amide
N
O
Amide
Synthesize withreaction chosenin Step 1
Randomly selecta reaction andretro-synthesize
HN
F
F
O
OH
H2NO OH
HN
F
F
O
OH
Step 2H2N
O OH
H2N
F
Randomly pick afragment and substituteby a fragment of thesame type
HN
Fragmented Parent Structure Fragmented Child Structure
(c) G. Schneider @ EuroMug 4/11/04, Cambridge, UK
Design Examples - Napsagatran
Napsagatran
OS NH
NH
N
H2NNH
O
NOH
O
OO
OS NH
NH
N
H2NNH
O
O
OOH
T = 0.9
• ‘recapped’ COBRA• Daylight Fingerprints• Tanimoto Coefficient• non-adaptive EA
(c) G. Schneider @ EuroMug 4/11/04, Cambridge, UK
Design Examples - Gleevec
• ‘recapped’ COBRA• Daylight Fingerprints• Tanimoto Coefficient• non-adaptive ESGleevec
NN
O
NH
NH
N
N
N
NN
O
NH
NH
N
N
NN
T = 0.88
NH
O N
NH
NNH
N
N
N
T = 0.87
(c) G. Schneider @ EuroMug 4/11/04, Cambridge, UK
Scaffold-Hopping & Combinatorial Design
N
O
R
N
O
CO2Et
N
F
R = H;Br;MeSO2;
clogP = 6.90clogP = 7.79clogP = 5.47
1
2
3
N
O
O
R
R'O
NR'
R
De novo design
CB-1 Seed (nM)(Khanolkar et al. 2000)
DBGPCR-BBRogers-Evans et al. (2004) QSAR Comb. Sci. 23:426
Focusedlibraries
(c) G. Schneider @ EuroMug 4/11/04, Cambridge, UK
Bioactivity of hCB-1 Focused Libraries
N
O
O
R
R'ONR'
R
6% Hit Rate 10% Hit Rate
R R’ IC50 (hCB-1) /µmol
Cl 4.0
tBu 4.0
tBu 9.0
O
*
*
*
Cl
R R’ IC50 (hCB-1) / µmol
2,4-CF3 0.6
4-Cl 3.0
H 6.0*
*
O
*O
CH2COCF3Ph
(c) G. Schneider @ EuroMug 4/11/04, Cambridge, UK
Scaffold-Hopping: Novel Kv1.5 Blockers
NH
NH OS
O
O
SNHO
O
NH
O
O
NHS
OHNH
O
OO
OIC50 < 1 µM(ICAGEN)
IC50 ~ 7 µM IC50 ~ 1 µM
IC50 < 1 µM
De novoDesign
De novoDesign
VirtualCombiChemVirtualCombiChem
SNHO
O
NH
O
Schneider et al. (2000) Angew. Chemie Int. Ed. 39:4130
PPP MatchingPPP Matching
(c) G. Schneider @ EuroMug 4/11/04, Cambridge, UK
Acknowledgements
Evgeny ByvatovProf. Holger Stark
Dr. Mark Rogers-EvansDr. Konrad BleicherDr. Alexander Alanine
Aventis Pharma Deutschland GmbH
Beilstein-Institut zur Förderung der Chemischen Wissenschaften
Daylight Chemical Information Systems Inc.F. Hoffmann-La Roche AG
Fonds der Chemischen Industrie (FCI)
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