Fragment-based de novo Design · Fragment-based Design • combinatorial optimization principle •...

(c) G. Schneider @ EuroMug 4/11/04, Cambridge, UK

Fragment-based de novo Design

Gisbert Schneider & Uli Fechner

[email protected]

Beilstein Endowed Chair for CheminformaticsInstitute of Organic Chemistry & Chemical BiologyJohann Wolfgang Goethe-UniversityFrankfurt, Germany


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)


• 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


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”


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)


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


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.


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


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


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


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*]


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


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


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


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


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


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


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)

Fragment-based de novo Design · Fragment-based Design • combinatorial optimization principle •...

Documents

Transcript of Fragment-based de novo Design · Fragment-based Design • combinatorial optimization principle •...