Combinatorial Chemistry

1

• Combinatorial Chemistry

2
(No Transcript)
3
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

5

• Conventional Synthesis

one educt (A) reacts with one educt (B) to yield
one product AB
6

• Combinatorial Synthesis

different building blocks of type A react
combinatorially with different building blocks
of type B to yield a combinatorial library
7

• Combinatorial Synthesis

A1B1 A1B2 A1B3
A1 A2 A3
B1 B2 B3
A2B1 A2B2 A2B3
A3B1 A3B2 A3B3
8

• 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

9

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

10

• Scaffold-based libraries
• (Example benzodiazepines)

11

• Scaffold-based libraries
• (Example benzodiazepines)

12
Backbone-based libraries (Example peptides)
13

• Basic characteristics of Combichem (III)
• Combinatorial Chemistry runs either
• on solid support ("solid phase chemistry")
• in solution ("solution phase chemistry")

14

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

15

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

16
The Split-Pool Synthesis Strategy
17
Array-based Synthesis Strategy
18
The Combinatorial Explosion
The Number of peptides increases exponentially
with the number of combinations
19

• The Split-Pool Synthesis Strategy

20

• 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

21

• How can we find the active component(s) of the
  library?

• Deconvolution (iterative or parallel)
• Microsequencing
• Tag-based encoding methods

22
Iterative Deconvolution
23
Parallel Deconvolution (Positional Scanning)
24
Microsequencing of peptides by Edman degradation
25
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

26
Chemical encoding tags for solid-phase synthesis
27
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
28
Tag analysis by electron capture GC (taken from
Ohlmeyer et al. PNAS 90, 1993, 10922-10926)
29
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

30
IRORI Kan - , Chiron Pin Technology
31
Biopolymers used in Combinatorial Chemistry
vinyl. Sulfonyl- peptides
Peptides
vinyl. Peptides
Peptoids
Oligo-carbamates
Oligosulfones
Oligo- ureas
Oligosulfoxides
32

• 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

33

• Some examples...

34
(No Transcript)
35
(No Transcript)
36

• Automation

37
Solid phase-combinatorial chemistry to prepare
single compounds
38
Schematic representation of a reaction block for
solid-phase synthesis
39
Solution-phase combinatorial chemistry
40
Automation I
Synthesis robot for solid-phase chemistry A
Reactor block B/C Reagent supplies D Robot
arm with pipetting needles
41
Automation II
Reactor block for solid or solution phase
synthesis A Reaction vessels B Teflon
device C Pipetting needles
42
Automation III
...more reaction blocks
43
Automation IV
"Igel" multipipetting synthesizer for solution
phase chemistry
44
Automation V
Fully automated synthesis robot from Accelab
GmbH
45

• Combinatorial Chemistry is more than just large
  numbers!
• systematic variation of substituents on a
  common template
• is a key feature of combinatorial chemistry

46

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

Variations in R1
Variations in R2
47
Combinatorial libraries