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Combinatorial Chemistry

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Dr. Hans Briem Einf hrung in die Arzneimittelforschung - Vorlesung WS 2001/2002 ... septum. polypropylene reactor vessels. polymer beads. filter. valve ... – PowerPoint PPT presentation

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Title: Combinatorial Chemistry


1
  • Combinatorial Chemistry

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The Lead Discovery Process
4
  • Basic characteristics of Combichem (I)
  • Combinatorial Chemistry prepares
  • a large number of different compounds
  • simultaneously
  • under identical reaction
  • in a systematic manner

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  • Conventional Synthesis

one educt (A) reacts with one educt (B) to yield
one product AB
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  • Combinatorial Synthesis

different building blocks of type A react
combinatorially with different building blocks
of type B to yield a combinatorial library
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  • Combinatorial Synthesis

A1B1 A1B2 A1B3
A1 A2 A3
B1 B2 B3
A2B1 A2B2 A2B3
A3B1 A3B2 A3B3
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  • Why Combinatorial Chemistry?
  • large numbers of compounds promise to increase
    the chance of finding hits/leads
  • "feed the hungry beast" of HTS
  • systematic variations increase the chance to find
    Structure-Activity Relationships (SAR)
  • hits can be followed up more rapidly

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  • Basic characteristics of Combichem (II)
  • Combinatorial Libraries can be structurally
    related by
  • a central core ("scaffold")
  • a common backbone

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  • Scaffold-based libraries
  • (Example benzodiazepines)

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  • Scaffold-based libraries
  • (Example benzodiazepines)

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Backbone-based libraries (Example peptides)
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  • Basic characteristics of Combichem (III)
  • Combinatorial Chemistry runs either
  • on solid support ("solid phase chemistry")
  • in solution ("solution phase chemistry")

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  • Basic characteristics of Combichem (IV)
  • Combinatorial Chemistry prepares either
  • mixtures ("combinatorial libraries") or
  • single compounds ("arrays")

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  • Mixtures vs. Arrays
  • The Split-Pool Synthesis Method to produce
    mixtures

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The Split-Pool Synthesis Strategy
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Array-based Synthesis Strategy
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The Combinatorial Explosion
The Number of peptides increases exponentially
with the number of combinations
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  • The Split-Pool Synthesis Strategy

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  • One bead - one substance concept
  • Each bead contains only one sort of product
    (50-200 pmol concentration)
  • Product can be screened either on bead or after
    cleavage from bead
  • Single beads can be spotted in microtiter plates
    or immobilized and screened individually

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  • How can we find the active component(s) of the
    library?
  • Deconvolution (iterative or parallel)
  • Microsequencing
  • Tag-based encoding methods

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Iterative Deconvolution
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Parallel Deconvolution (Positional Scanning)
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Microsequencing of peptides by Edman degradation
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Tag-based encoding methods
Encoding principle
  • each individual bead contains an encoding tag
  • each tag uniquely encodes the building blocks
    on the bead

Encoding tags in use
  • DNA (analysis by PCR)
  • Peptides (analysis by Edman degradation)
  • Haloaromatic groups (suitable for "binary code")
  • Secondary amides (suitable for "binary code")
  • Radiofrequency transponders

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Chemical encoding tags for solid-phase synthesis
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Example of chemical "binary code" (taken from
Ohlmeyer et al. PNAS 90, 1993, 10922-10926)
Binary translation table Ser (S) 001 Ile
(I) 010 Lys (K) 011 Leu (L) 100 Gln (Q)
101 Glu (E) 110 Asp (D) 111
Sequence E Q K L I
S Binary Code 110 101 011 100 010 001
Tags T18 ... T1
"1" in binary code means "tag is present" "0" in
binary code means "tag is absent"
Peptide Sequence E Q K L I S Tag
Sequence T18 T17 T15 T13 T11 T10 T9 T5 T1
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Tag analysis by electron capture GC (taken from
Ohlmeyer et al. PNAS 90, 1993, 10922-10926)
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Encoding by Radiofrequency chips
  • Synthesis by Split-and-Pool principle
  • Polymer beads are located in a microreactor
    vessel
  • Each microreactor vessel contains one
    semi-conductor chip
  • Unique radiofrequency signals can be recorded
    and detected

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IRORI Kan - , Chiron Pin Technology
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Biopolymers used in Combinatorial Chemistry
vinyl. Sulfonyl- peptides
Peptides
vinyl. Peptides
Peptoids
Oligo-carbamates
Oligosulfones
Oligo- ureas
Oligosulfoxides
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  • Non-polymeric combinatorial libraries
  • Since biopolymers are often not "drug-like",
    efforts have been made to synthesize single,
    "drug-like" molecules combinatorially
  • Solid-phase or solution phase synthesis is
    possible for a wide variety of organic reactions
  • Automation support synthesis

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  • Some examples...

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  • Automation

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Solid phase-combinatorial chemistry to prepare
single compounds
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Schematic representation of a reaction block for
solid-phase synthesis
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Solution-phase combinatorial chemistry
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Automation I
Synthesis robot for solid-phase chemistry A
Reactor block B/C Reagent supplies D Robot
arm with pipetting needles
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Automation II
Reactor block for solid or solution phase
synthesis A Reaction vessels B Teflon
device C Pipetting needles
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Automation III
...more reaction blocks
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Automation IV
"Igel" multipipetting synthesizer for solution
phase chemistry
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Automation V
Fully automated synthesis robot from Accelab
GmbH
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  • Combinatorial Chemistry is more than just large
    numbers!
  • systematic variation of substituents on a
    common template
  • is a key feature of combinatorial chemistry

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  • The systematic variation of substituents
  • is ideally suited to explore SAR patterns of
    hits found
  • in combichem libraries

Variations in R1
Variations in R2
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Combinatorial libraries
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