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Combinatorial chemistry - HTS and its applications in drug discovery
Combinatorial chemistry - HTS and its applications in drug discovery
1) In 1960-combinatorial chemistry was
                           introduced.
                        2) The drug discovery process become highly
                           parallel.
                        3) Even thousands of structures could be
                           synthesised one at a time.
                        4) Interestingly biologist introduced HTS to
                           perform invitro assays.

 In 1963,combinatorial synthesis of peptide on resin bead was done by Bruce
  Merrifield.

 It is a tool which allows large no of compounds to be synthesized simultaneously in a
  time taken to prepare only handful of compounds by traditional synthesis.

 A chosen set of building blocks are reacted together to make a collection of products
  known as “library” or “an array”.
A1                    B1




           A2                    B2




           An                     Bn


• The structure of the compounds in the mixture are not known with certainty
• They are not separated instead each mixture is tested for biological activity as a
  whole & if active the mixture is analyzed for active compound.
Combinatorial chemistry - HTS and its applications in drug discovery
Combinatorial
                                         synthesis

                                                         Solution phase
                          Solid phase synthesis
                                                            synthesis

 Parallel   Mix & split     Tea bag    Multi-pin    Laminar       microchip-
synthesis   technique      synthesis   synthesis   solid phase   spacial array
Combinatorial chemistry - HTS and its applications in drug discovery
1. In this method ,the reaction is carried out on a solid
   support such as resin beads.
2. The solid phase synthesis was pioneered by
   Merrifield –synthesis of peptides.



 The bead is treated with different starting materials
  which bound together.
 Then it is mixed with another reagent to get the
  product which is bound to solid support.
 The excess reagent or by product can be easily
  removed by washing with appropriate solvent.
A cross linked insoluble polymeric
 support-resin.
An anchor or linker covalently linked
 to resin.
A bond linking the substrate to linker
 which will be stable to reaction
 condition.
Chemical protecting groups for
 protecting the functional group not
 involved in the synthesis.
RESIN
        LINKER   FUNCTIONAL
                 GROUP
BEAD
1.Polystyrene resins
2.Tentagel resins
3.Pepsyn
4.PEGA
5.Glass and ceramic beads
The linker is the molecule that site between the
 compound and the support.

The linker moves the point of attachment of
 substrate away from the surface of the bead.

Different linkers are used depending on the

       functional group(which is present on the
                      substrate)

       functional group(which is desired on the final
                      product once it is released)
WANG RESIN: linker suitable
RESIN       LINKER                F   for attachment & release of
                                      carboxylic acids.
                             OH
              O




RESIN       LINKER                F   MERRIFIELD RESIN : linker
                                      suitable for peptide products.

                            O
                      O




                                      RINK RESIN : Linker suitable
RESIN       LINKER                F   for attachment & release
                                      of carboxamide.
                     NH2
        O
                            OMe

                      MeO
Protecting groups are important for blocking
& regenerating certain functional groups in a
             reaction sequence.

Some example of protecting groups are
    FMOC(fluoro methoxy carbonyl)
    TBOC(tertiary butyloxy carbonyl)
R2
               HO                [BOC]
                             N
O                            H           O                 R2
                    O                             H
     NH 2                                         N                  [BOC]
                                                                N
                                                                H
    R1                                       R1        O
                                                           peptide
                                                               F3C-COOH
                                                                N-Et3

                                             O                  R2
                                                       H
                                                       N
    [REPEAT]                                                         NH 2
                                                  R1       O
Here the compounds are synthesised in separate vessels but at
 the same time parallel.

The array of reactions are taken either in
      grid well in a plastic plate(in bead method)
                      or
      pins(grid of plastic rods) called crowns.
The building blocks are attached to these beads or crowns.

The structure of product is identified from the grid code.
A bath of resin is divided in to equal portion in reaction
vessel.

Each portion of resin is treated with treated with
different derivative of first block(A,B & C).

After washing the beads are pooled together in one pot
& mixed thoroughly.

Then split in to equal portion again for coupling to the
next portion.

This process is continued until the required library is
synthesised.
A           B       C




    A           A       A
    B           B       B
    C           C       C




A   A       B   A       A

    B       B   B       B
    C       B   C       C
Combinatorial chemistry - HTS and its applications in drug discovery
Combinatorial chemistry - HTS and its applications in drug discovery
Combinatorial chemistry - HTS and its applications in drug discovery
SEAL



POLYPROPYLENE
MESH




 RESIN
The reaction vessel consists of brush like
array of pins, at the end of it consists of bead
   (lollypop) with suitable linker. Here the
            synthesis takes place.


   It is inserted in to the plates where the
reagents & the solvents kept ,and continously
                    changed.
Combinatorial chemistry - HTS and its applications in drug discovery
Combinatorial chemistry - HTS and its applications in drug discovery
Spatial array of microchips , which is
    embedded with resin beads
Combinatorial chemistry - HTS and its applications in drug discovery
Combinatorial chemistry - HTS and its applications in drug discovery
Combinatorial chemistry - HTS and its applications in drug discovery
Unlike one bead - one compound synthesis
,solution phase synthesis often lead to mixture of
products in one pool.

Most of the org reaction occurs in solution phase .
For this reason there has been much interest in
solution phase synthesis.

The main problem here is the difficulty of removing
unwanted impurities at each step in synthesis.
Combinatorial chemistry - HTS and its applications in drug discovery
Combinatorial chemistry - HTS and its applications in drug discovery
R-CO-Cl + RI-NH2         R-CO-NH-RI + HCl


Acid chloride based set:-

A1 + (B1,B2,B3…………B10)        mixture1 containing all possible A1-B compounds
A2 + (B1,B2,B3…………B10)        mixture2 containing all possible A2-B compounds


A10+(B1,B2,B3…….B10)        mixture10 containing all possible A10-B compounds

Amine based set:-

B1 + (A1,A2,A3…………A10)         mixture1 containing all possible B1-A compounds
B2 + (A1,A2,A3…………A10)         mixture2 containing all possible B2-A compounds


B10+(A1,A2,A3…….A10)           mixture10 containing all possible B10-Acompounds
R1    COOH          R2            NH2       R3       CHO        NC



                         O             R3        H

                                                 N
                    R1            N
                                  R2         O




          OH             O        R3             R5        R4        R2
OR                                         OH                        N    R3
                O   R1       N                        N     R3
 OR                                              R1
               R2                                                N
      R1                     R2        O              R2             O
POOL
A subset of a given combinatorial library.
The process of combining & mixing library
component.
BUILDING BLOCKS: One of a set of
interchangable reagents that can be used in
synthesis of library.

DECONVOLUTION
Isolation & identification of the most active
compound in a mixture is known as
deconvolution.
1)   One bead one compound strategy
2)   Iterative deconvolution
3)   Subtractive deconvolution
4)   Bogus coin deconvolution
5)   Orthogonal pooling
6)   Positional scanning
It is the process as a result of which the combinatorial
exp becomes less complex.

It is usually done by backtracking & reanalysing or
resynthesising a subset of structures in the library.

The goal of deconvolution is to determine which of
the mixture of compounds is actually responsible for
the activity.

Eg: micromanipulation & sequential release.
The specific quantity of beads are allocated
for each possible structure in library.ie beads
contains only molecules of the library
member. They may be tagged.
      The advantage of this is simplicity of
analysis & screening.
Advances in robotics & automation reduces
problems in this strategy.
This is same as mix and split technique.
At each gp of beads bearing a variety of
compounds,but a given structure only appears in one
group.
In this a small library of structures selected &
screened.
We find activity in the middle gp of beads ie
BAC,BBC,BCC….This tells us that in position ‘1’,B is
essential for the activity.
The final step is to synthesise this beaded
compounds,keeping then separate & screened each &
find out ‘BAC’ IS THE ACTIVE ONE
This is similar to iterative deconvolution but
uses negative logic ie eliminate a functional
group if activity is absent.
Thus functional group that is missing must be
needed for activity.
It is useful for “QSAR” studies.
Example:chlorine gp is placed in several position of
phenyl ring.
1) The entire library is screened to get baseline
   activity level.
2) If activity is detected,a set of sub library is
   prepared,each with subtraction of functional
   group & screened to identify most important
   functional group.
3) The reduced library contains only these
   functional gp,these are screened to get the
   active compound.
 The term “orthogonal” means perpendicular
In this type of pooling ,we distribute the functional
groups to be considered in to a set of sub
libraries, A,B,C…etc. which can contain mixture of
same compounds also.
But the functional groups distributed such that any
subset in A & B shares only one functional gp.

      eg: if we have a very small library of structures-
aa,ab,ac……
A                  B                 C
(aa,ab)            (aa,ac)          (ab,ac)




  Shows the pharmacological activity


      ‘ab’ is the active compound
This is a non iterative screening in which a sub set
library is created with a single building block fixed at one
position & all other building blocks in other position.

Here by selecting the functional group from the most
active subset at each position ,the most active
compound is over all discovered.
Encoding/tagging used as a code to indicate what
happened at each step in the synthesis ,thus identify
   the structure of most active library member.



                        TAGGING



                                              LASER
 CHEMICAL     ISOTOPIC DYE
                              R.F.TAGGING    OPTICAL
 TAGGING        TAGGING
                                            ENCODING
Here specific compounds (tags) are used as a code for
           the individual step in synthesis.
Eg :ss DNA(oligonucleotide) 6 bases are used for DNA
 generic code .For decoding, DNA tag is amplified by
                        PCR.



                  --A—B—C—B—C--etc        Library compound

                  --R—S—T—S—T--etc         Code compound
COLOURED DYE WITH ISOTOPIC LABELLING
Combinatorial chemistry - HTS and its applications in drug discovery
A tiny micro chip is added to resin/to solution.

As the various reactions are conducted to
generate the product,at each step a rf signal is
stored in microchip.

This signal can be recalled to identify the
sequence of reaction that generated the product.
The tags are encapsulated in glass casing which is stable to chemical &
synthetic conditions.
Each tag code is associated with the identity of its library member &
detected by data base computer.
Here the solid support acts as an eye to view the reaction
The solid support consists of a ceramic chip
covered with a polypropylene-poly styrene
polymer in which barcode pattern is burned at
each step & is decoded visually with the use of
a microscope.
Combinatorial chemistry - HTS and its applications in drug discovery
HPLC
IR SPECTRA
NMR SPECTRA
MASS SPECTRA
UV-VISIBLE SPECTRA
1) Chemically cleave the compounds from the support & filter
   off the beads
2) The filter the solution to get the product.
3) If the solution contains just a single compound we use
                   • IR
                   • UV
                   • MASS
                                                SPECTROPHOTOMETER
                   • FLUORESCENCE
                   • NMR
                       If it contains a mixture we use HPLC
HPLC is highly effective method for separation & detection of components
Combinatorial chemistry - HTS and its applications in drug discovery
Combinatorial chemistry - HTS and its applications in drug discovery
Combinatorial chemistry - HTS and its applications in drug discovery
•IR light is transparent to resin beads ,hence we can analyse
the resin bead directly without cleaving the product from it.

•FTIR will amplify the very small spectral signal from one or
more beads.

•The shape of the beads affect the IR spectra,flattned beads
gives strong signal than spherical beads.
Combinatorial chemistry - HTS and its applications in drug discovery
Combinatorial chemistry - HTS and its applications in drug discovery
NMR gives more structural informations
than IR/UV.

The solid support broadens the peak &
hence low resolution.

Magic angle spinning NMR: Here the
sample is inserted in to the mag.field at the
angle of 550 ,this will reduce the peak
broadening,and has been used to analyse
swollen polymer beads directly.
Combinatorial chemistry - HTS and its applications in drug discovery
MASS spectroscopy analysis is highly automated.

The measurement is made on resin beads directly.

It is the most widely used technique in combinatorials.
Combinatorial chemistry - HTS and its applications in drug discovery
Solution containing compounds is passed
through electrically charged capillary & they
“explore” in to smaller droplets.
Combinatorial chemistry - HTS and its applications in drug discovery
The sample is embedded in the solid matrix(2,5 dihydroxy
benzoic acid)
Bombarded with laser
The sample molecule are vaporized &ionised
The analysis is done with the use of time of flight
analyser(TOF)
        In TOF ions of different mass travels different distance in
a specified of time.
Combinatorial chemistry - HTS and its applications in drug discovery
Combinatorial chemistry - HTS and its applications in drug discovery
Colourimetric detection:
Wavelenght ranges from 400-800 nm
UV SPECTRA ranges from 200-400nm.
Principle:Beer’s-Lambert’s law.
Lamda max-used as qualitative aspect
Combinatorial chemistry - HTS and its applications in drug discovery
Combinatorial chemistry - HTS and its applications in drug discovery
In recent years the peptide-protien & peptide-antibody
interactions have gained importance in the area of autoimmune
diseases.

By using combinatorials a library of hexa peptides was generated
& screened for B7 antibodies binding with CD-2 T-cell proliferation.

Peptides screened for inhibition of T cell for type 1-DM & RA.

Certain polypeptide screened for inhibition of kinase & protease
for AIDS &cancer.
Peptide suffer from disadvantages like poor bioavailability &
unfavorable ph.kinetic profile.
Thus the focus has shifted to synthetic peptido-mimetics like
peptoids.

 Peptoids are molecules in which the variation
 occurs in the attachment of amide nitrogen.


Similarity:                       Difference:

Molecular weight <500             Lack peptide H-bond
                                   More rational flexibility
Side chain,functional gps         More stability
in same position.                  Less double bond
O       R1                O       R3
                     H
                     N
        N                         N
        H                         H
                 O       R2



    O       R1                O       R3
            N                         N
                         N
                 O       R2

Peptoids are N substituted glycine with increased biological
half life.
O

    O               NH2
H
N
        N
            O
Combinatorial chemistry - HTS and its applications in drug discovery
oIn contrast to biopolymers,synthetic oligomers are stable to
proteases & nucleases.

oThey may be linear chain molecules like
      oligo nucleotide(ssDNA & ssRNA)
      oligo ureases.

oA library of 5000 oligo peptoids was generated & screened for
7-transmembrane G protien coupled receptor inhibition.certain
peptoids were active at nano mol conc.
Combinatorial chemistry - HTS and its applications in drug discovery
Solid phase chemistry can also synthesise oligo
saccharides.
Carbohydrate antibiotics including vancomycin
& aminoglycosides has been target in
combinatorial chemistry.
Examples
Bauhinia purpurea “lectin” analogues.
Erythromycin analogues.
Neocarzinostatin analogues.
R2             NH-FMOC
                                                                       NH2
                   O                              R2
                                                                         O
  HO
                                                       O

                               R1                                            R1

    2 amino benzophenone
                                             Solid support:tenta gel



                                                           R2                NH2
                       H
                                    O                                          O
                           N                                    O
          R2
                                        R3
            O                                                                      R1

                                R1
Benzodiazepine
CO                                          CONH2
           NH                 CO   NH
                 RCOCl                  RSO2Cl

                CH2Cl2             OH                 OSO2R1
H2N        OH            HN               RCONH
                         CO
                         R
Uses:leukotriene antagonist ,carbapenam
antibiotics etc.
Combinatorial chemistry - HTS and its applications in drug discovery
It involves identification &
validation of target & docking to
identify the hit drug.

Virtual libraries are created in
combinatorial manner to screen
the molecules.

This helps to find out novel
drugs against sp.diseases.
Combinatorial chemistry - HTS and its applications in drug discovery
Virtual library: a combinatorial library that has no
physical existance,it exists in computer & can be
generated automatically.

They are screened againt “rule of 5” or to be docked by
using molecular docking.
CADD is a combination of
computational chemistry and
information technology tools that help
us to discover new therapeutic
solutions.
ADVANTAGES
target specific & structure based
 fast and automatic
 very low cost
 high success rate
Two types:
Ligand based drug design
Structure/receptor based drug
design
Combinatorial chemistry - HTS and its applications in drug discovery
Combinatorial synthesis is now being used in lead
optimsation program of many potent drugs of natural
origin.
Eg:Rhodacyanin:
It is a natural dye with anti malarial activity. it is
considered as a lead to develop new anti malarials
effective againt quinine resistant plasmodium.
In lead optimisation process,Takasu et al,reported a
simple one pot method for synthesis of no of
rhodacyanin analogue with variation in “N” containing
ring.
R
            S           S
N
    S                       OHC   N
                N
        O           R             R1
Combinatorial chemistry - HTS and its applications in drug discovery
Nucleoside analogue are useful as
antimetabolites & treatment of cancer.
By using combinatorial approach,the
synthesis of several nucleoside has been
synthesised.
These are effective againts various cancers.

Green Burg et al developed a method of
synthesis of nucleosides in solid state which
are the building blocks for antisense
polynucleotide.
R1
                                N                R1
                   N
 R                                                     N
          O   G                     N        N
                       N
                                                           N
                                                 N
HO            OH
                                         R   O
 R1

      N                                 HO            OH

 N        O
 H
                   R1

                        N

                   N        O
 R        O

                            PYRAMIDINE NUCLEOTIDE
HO            OH
Automated ,microprocessor controlled robotic process called as HTS.
HIGH THROUHGPUT SCREENING
Automated microprocessor controlled robotic process
HTS : 50000-100000 compounds can be screened per week
 against biological target
u HTS : 10000-100000 compounds within 24hrs
HTS assay system consist of sample wells for handling samples
   CHEMICAL LIBRARY
   HTS ASSAYS
   INFORMATICS AND ANALYSIS
   PROCESS ENGINEERING
MICROPLATE TECHNOLOGIES

a.96 well microtiter plate
        8 rows (A-H)
        12 columns
        88 test samples
        8 controls
b. 384 well microtiter plate
        16 rows (A-P)
        24 columns
        352 test samples
        32 controls
c. 1536 well microtiter plate
       32 rows ( A-AF)
       48 columns
       1,408 test samples
       128 controls
IN VITRO MARTIX –
PHARMACODYNAMIC         LIGAND
     STUDIES         INTERACTION
                        STUDIES



PHARMACOKINETIC   NATURAL PRODUCT
    STUDIES          ISOLATION




  METABOLISM
                  DRUG SYNTHESIS
   STUDIES
Here an effective target is identified & validated
for its function.

HIT: it is a molecule with confirmed activity
from primary hts assay,with good profile in 20
assays & with confirmed structure.

LEAD: Lead is explained as a hit series for which
SAR is studied.
Fl.correlation
                spectroscopy


Scintillation
 proximity                       Fl.anisotropy
 assay(SPA)




   Surface                       Fl.resonance
  sensitive                          energy
fl.detection                        transfer


                Fl.life time
                 imaging
                microscopy
This procedure is suitable to detect receptor
          ligand binding reactions.
Combinatorial chemistry - HTS and its applications in drug discovery
The molecular interactions of drug & the receptor
will give rise to measurable fluctuations in FI.
When two different chromophores(drug & receptor) interact via
  dipole-dipole mechanism, transfers excitation energy non
              radially to acceptor chromophore.
Combinatorial chemistry - HTS and its applications in drug discovery
The sample is illuminated with pulsed laser
 & the life time of fl.probe is determined
from the phase shift between the
modulation of excitation light & emission of
flourescence.
Eg: measurement of tyrosine kinase activity.
Combinatorial chemistry - HTS and its applications in drug discovery
The membrane receptor can be immobilised using
affinity tags

Thus flourescence labelled ligand binds with it then
the receptor emits fluorescence.

Eg:flourescence antagonist on immobilized 5-HT3a
receptor.
An antibody or a receptor
 molecule, which is bound to a bead
emits light when beta emission from an
 isotope occurs in close proximity; ie
 when a radiolabelled ligand binds to
   bead with receptor or antibody .
Combinatorial chemistry - HTS and its applications in drug discovery
Combinatorial chemistry - HTS and its applications in drug discovery
Absorption studies: caco(colon
cancer)cell line
 grow confluently & form a monolayer on
polycarbonate support or collagen coated
polycarbonate support. These are used
for permeation studies.
Combinatorial chemistry - HTS and its applications in drug discovery
Due to development of 2-D multi parallel HPLC
(SEPBOX,SEPIAtec,Germany) it is now possible
to load up to 5g of NP extract & to isolate all
compounds in 70-80% purity with in 24hrs.
SEPBOX system works by using gradient elution & polarity based
trapping in solid phase extraction(SPE).

SEPBOX is coupled with photodiode array detector & light
scattering detector in series enables the identification &
quantification of the significant compounds.

NP database containing about 10,000 structurally characterized
natural compounds ,is being commercialized using MS & 2-D
NMR.
1. Modern methods of drug discovery by
   A.Hillisch and R.Hilgenfeld page no: 72-98
2. Foye’s Medicinal chemistry by Thomas and
   David page no: 56-43
3. Medicinal chemistry by K.Illango page no: 389-407
4. http://www.sciencedirect.com/science
5. http://www.liebertonline.com/loi/adt
6. http://www.ingentaconnect.com/content
7. http://jbx.sagepub.com
8. http://www.nature.com/nmeth/index.html
9. http://mli.nih.gov/
10. http://pubchem.ncbi.nlm.nih.gov/
Combinatorial chemistry - HTS and its applications in drug discovery

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Combinatorial chemistry - HTS and its applications in drug discovery

  • 3. 1) In 1960-combinatorial chemistry was introduced. 2) The drug discovery process become highly parallel. 3) Even thousands of structures could be synthesised one at a time. 4) Interestingly biologist introduced HTS to perform invitro assays.  In 1963,combinatorial synthesis of peptide on resin bead was done by Bruce Merrifield.  It is a tool which allows large no of compounds to be synthesized simultaneously in a time taken to prepare only handful of compounds by traditional synthesis.  A chosen set of building blocks are reacted together to make a collection of products known as “library” or “an array”.
  • 4. A1 B1 A2 B2 An Bn • The structure of the compounds in the mixture are not known with certainty • They are not separated instead each mixture is tested for biological activity as a whole & if active the mixture is analyzed for active compound.
  • 6. Combinatorial synthesis Solution phase Solid phase synthesis synthesis Parallel Mix & split Tea bag Multi-pin Laminar microchip- synthesis technique synthesis synthesis solid phase spacial array
  • 8. 1. In this method ,the reaction is carried out on a solid support such as resin beads. 2. The solid phase synthesis was pioneered by Merrifield –synthesis of peptides.  The bead is treated with different starting materials which bound together.  Then it is mixed with another reagent to get the product which is bound to solid support.  The excess reagent or by product can be easily removed by washing with appropriate solvent.
  • 9. A cross linked insoluble polymeric support-resin. An anchor or linker covalently linked to resin. A bond linking the substrate to linker which will be stable to reaction condition. Chemical protecting groups for protecting the functional group not involved in the synthesis.
  • 10. RESIN LINKER FUNCTIONAL GROUP BEAD
  • 12. The linker is the molecule that site between the compound and the support. The linker moves the point of attachment of substrate away from the surface of the bead. Different linkers are used depending on the functional group(which is present on the substrate) functional group(which is desired on the final product once it is released)
  • 13. WANG RESIN: linker suitable RESIN LINKER F for attachment & release of carboxylic acids. OH O RESIN LINKER F MERRIFIELD RESIN : linker suitable for peptide products. O O RINK RESIN : Linker suitable RESIN LINKER F for attachment & release of carboxamide. NH2 O OMe MeO
  • 14. Protecting groups are important for blocking & regenerating certain functional groups in a reaction sequence. Some example of protecting groups are FMOC(fluoro methoxy carbonyl) TBOC(tertiary butyloxy carbonyl)
  • 15. R2 HO [BOC] N O H O R2 O H NH 2 N [BOC] N H R1 R1 O peptide F3C-COOH N-Et3 O R2 H N [REPEAT] NH 2 R1 O
  • 16. Here the compounds are synthesised in separate vessels but at the same time parallel. The array of reactions are taken either in grid well in a plastic plate(in bead method) or pins(grid of plastic rods) called crowns. The building blocks are attached to these beads or crowns. The structure of product is identified from the grid code.
  • 17. A bath of resin is divided in to equal portion in reaction vessel. Each portion of resin is treated with treated with different derivative of first block(A,B & C). After washing the beads are pooled together in one pot & mixed thoroughly. Then split in to equal portion again for coupling to the next portion. This process is continued until the required library is synthesised.
  • 18. A B C A A A B B B C C C A A B A A B B B B C B C C
  • 23. The reaction vessel consists of brush like array of pins, at the end of it consists of bead (lollypop) with suitable linker. Here the synthesis takes place. It is inserted in to the plates where the reagents & the solvents kept ,and continously changed.
  • 26. Spatial array of microchips , which is embedded with resin beads
  • 30. Unlike one bead - one compound synthesis ,solution phase synthesis often lead to mixture of products in one pool. Most of the org reaction occurs in solution phase . For this reason there has been much interest in solution phase synthesis. The main problem here is the difficulty of removing unwanted impurities at each step in synthesis.
  • 33. R-CO-Cl + RI-NH2 R-CO-NH-RI + HCl Acid chloride based set:- A1 + (B1,B2,B3…………B10) mixture1 containing all possible A1-B compounds A2 + (B1,B2,B3…………B10) mixture2 containing all possible A2-B compounds A10+(B1,B2,B3…….B10) mixture10 containing all possible A10-B compounds Amine based set:- B1 + (A1,A2,A3…………A10) mixture1 containing all possible B1-A compounds B2 + (A1,A2,A3…………A10) mixture2 containing all possible B2-A compounds B10+(A1,A2,A3…….A10) mixture10 containing all possible B10-Acompounds
  • 34. R1 COOH R2 NH2 R3 CHO NC O R3 H N R1 N R2 O OH O R3 R5 R4 R2 OR OH N R3 O R1 N N R3 OR R1 R2 N R1 R2 O R2 O
  • 35. POOL A subset of a given combinatorial library. The process of combining & mixing library component. BUILDING BLOCKS: One of a set of interchangable reagents that can be used in synthesis of library. DECONVOLUTION Isolation & identification of the most active compound in a mixture is known as deconvolution.
  • 36. 1) One bead one compound strategy 2) Iterative deconvolution 3) Subtractive deconvolution 4) Bogus coin deconvolution 5) Orthogonal pooling 6) Positional scanning
  • 37. It is the process as a result of which the combinatorial exp becomes less complex. It is usually done by backtracking & reanalysing or resynthesising a subset of structures in the library. The goal of deconvolution is to determine which of the mixture of compounds is actually responsible for the activity. Eg: micromanipulation & sequential release.
  • 38. The specific quantity of beads are allocated for each possible structure in library.ie beads contains only molecules of the library member. They may be tagged. The advantage of this is simplicity of analysis & screening. Advances in robotics & automation reduces problems in this strategy.
  • 39. This is same as mix and split technique. At each gp of beads bearing a variety of compounds,but a given structure only appears in one group. In this a small library of structures selected & screened. We find activity in the middle gp of beads ie BAC,BBC,BCC….This tells us that in position ‘1’,B is essential for the activity. The final step is to synthesise this beaded compounds,keeping then separate & screened each & find out ‘BAC’ IS THE ACTIVE ONE
  • 40. This is similar to iterative deconvolution but uses negative logic ie eliminate a functional group if activity is absent. Thus functional group that is missing must be needed for activity. It is useful for “QSAR” studies.
  • 41. Example:chlorine gp is placed in several position of phenyl ring. 1) The entire library is screened to get baseline activity level. 2) If activity is detected,a set of sub library is prepared,each with subtraction of functional group & screened to identify most important functional group. 3) The reduced library contains only these functional gp,these are screened to get the active compound.
  • 42.  The term “orthogonal” means perpendicular In this type of pooling ,we distribute the functional groups to be considered in to a set of sub libraries, A,B,C…etc. which can contain mixture of same compounds also. But the functional groups distributed such that any subset in A & B shares only one functional gp. eg: if we have a very small library of structures- aa,ab,ac……
  • 43. A B C (aa,ab) (aa,ac) (ab,ac) Shows the pharmacological activity ‘ab’ is the active compound
  • 44. This is a non iterative screening in which a sub set library is created with a single building block fixed at one position & all other building blocks in other position. Here by selecting the functional group from the most active subset at each position ,the most active compound is over all discovered.
  • 45. Encoding/tagging used as a code to indicate what happened at each step in the synthesis ,thus identify the structure of most active library member. TAGGING LASER CHEMICAL ISOTOPIC DYE R.F.TAGGING OPTICAL TAGGING TAGGING ENCODING
  • 46. Here specific compounds (tags) are used as a code for the individual step in synthesis. Eg :ss DNA(oligonucleotide) 6 bases are used for DNA generic code .For decoding, DNA tag is amplified by PCR. --A—B—C—B—C--etc Library compound --R—S—T—S—T--etc Code compound
  • 47. COLOURED DYE WITH ISOTOPIC LABELLING
  • 49. A tiny micro chip is added to resin/to solution. As the various reactions are conducted to generate the product,at each step a rf signal is stored in microchip. This signal can be recalled to identify the sequence of reaction that generated the product.
  • 50. The tags are encapsulated in glass casing which is stable to chemical & synthetic conditions. Each tag code is associated with the identity of its library member & detected by data base computer.
  • 51. Here the solid support acts as an eye to view the reaction
  • 52. The solid support consists of a ceramic chip covered with a polypropylene-poly styrene polymer in which barcode pattern is burned at each step & is decoded visually with the use of a microscope.
  • 54. HPLC IR SPECTRA NMR SPECTRA MASS SPECTRA UV-VISIBLE SPECTRA
  • 55. 1) Chemically cleave the compounds from the support & filter off the beads 2) The filter the solution to get the product. 3) If the solution contains just a single compound we use • IR • UV • MASS SPECTROPHOTOMETER • FLUORESCENCE • NMR If it contains a mixture we use HPLC
  • 56. HPLC is highly effective method for separation & detection of components
  • 60. •IR light is transparent to resin beads ,hence we can analyse the resin bead directly without cleaving the product from it. •FTIR will amplify the very small spectral signal from one or more beads. •The shape of the beads affect the IR spectra,flattned beads gives strong signal than spherical beads.
  • 63. NMR gives more structural informations than IR/UV. The solid support broadens the peak & hence low resolution. Magic angle spinning NMR: Here the sample is inserted in to the mag.field at the angle of 550 ,this will reduce the peak broadening,and has been used to analyse swollen polymer beads directly.
  • 65. MASS spectroscopy analysis is highly automated. The measurement is made on resin beads directly. It is the most widely used technique in combinatorials.
  • 67. Solution containing compounds is passed through electrically charged capillary & they “explore” in to smaller droplets.
  • 69. The sample is embedded in the solid matrix(2,5 dihydroxy benzoic acid) Bombarded with laser The sample molecule are vaporized &ionised The analysis is done with the use of time of flight analyser(TOF) In TOF ions of different mass travels different distance in a specified of time.
  • 72. Colourimetric detection: Wavelenght ranges from 400-800 nm UV SPECTRA ranges from 200-400nm. Principle:Beer’s-Lambert’s law. Lamda max-used as qualitative aspect
  • 75. In recent years the peptide-protien & peptide-antibody interactions have gained importance in the area of autoimmune diseases. By using combinatorials a library of hexa peptides was generated & screened for B7 antibodies binding with CD-2 T-cell proliferation. Peptides screened for inhibition of T cell for type 1-DM & RA. Certain polypeptide screened for inhibition of kinase & protease for AIDS &cancer.
  • 76. Peptide suffer from disadvantages like poor bioavailability & unfavorable ph.kinetic profile. Thus the focus has shifted to synthetic peptido-mimetics like peptoids. Peptoids are molecules in which the variation occurs in the attachment of amide nitrogen. Similarity: Difference: Molecular weight <500 Lack peptide H-bond More rational flexibility Side chain,functional gps More stability in same position. Less double bond
  • 77. O R1 O R3 H N N N H H O R2 O R1 O R3 N N N O R2 Peptoids are N substituted glycine with increased biological half life.
  • 78. O O NH2 H N N O
  • 80. oIn contrast to biopolymers,synthetic oligomers are stable to proteases & nucleases. oThey may be linear chain molecules like oligo nucleotide(ssDNA & ssRNA) oligo ureases. oA library of 5000 oligo peptoids was generated & screened for 7-transmembrane G protien coupled receptor inhibition.certain peptoids were active at nano mol conc.
  • 82. Solid phase chemistry can also synthesise oligo saccharides. Carbohydrate antibiotics including vancomycin & aminoglycosides has been target in combinatorial chemistry. Examples Bauhinia purpurea “lectin” analogues. Erythromycin analogues. Neocarzinostatin analogues.
  • 83. R2 NH-FMOC NH2 O R2 O HO O R1 R1 2 amino benzophenone Solid support:tenta gel R2 NH2 H O O N O R2 R3 O R1 R1 Benzodiazepine
  • 84. CO CONH2 NH CO NH RCOCl RSO2Cl CH2Cl2 OH OSO2R1 H2N OH HN RCONH CO R Uses:leukotriene antagonist ,carbapenam antibiotics etc.
  • 86. It involves identification & validation of target & docking to identify the hit drug. Virtual libraries are created in combinatorial manner to screen the molecules. This helps to find out novel drugs against sp.diseases.
  • 88. Virtual library: a combinatorial library that has no physical existance,it exists in computer & can be generated automatically. They are screened againt “rule of 5” or to be docked by using molecular docking.
  • 89. CADD is a combination of computational chemistry and information technology tools that help us to discover new therapeutic solutions. ADVANTAGES target specific & structure based  fast and automatic  very low cost  high success rate Two types: Ligand based drug design Structure/receptor based drug design
  • 91. Combinatorial synthesis is now being used in lead optimsation program of many potent drugs of natural origin. Eg:Rhodacyanin: It is a natural dye with anti malarial activity. it is considered as a lead to develop new anti malarials effective againt quinine resistant plasmodium. In lead optimisation process,Takasu et al,reported a simple one pot method for synthesis of no of rhodacyanin analogue with variation in “N” containing ring.
  • 92. R S S N S OHC N N O R R1
  • 94. Nucleoside analogue are useful as antimetabolites & treatment of cancer. By using combinatorial approach,the synthesis of several nucleoside has been synthesised. These are effective againts various cancers. Green Burg et al developed a method of synthesis of nucleosides in solid state which are the building blocks for antisense polynucleotide.
  • 95. R1 N R1 N R N O G N N N N N HO OH R O R1 N HO OH N O H R1 N N O R O PYRAMIDINE NUCLEOTIDE HO OH
  • 96. Automated ,microprocessor controlled robotic process called as HTS.
  • 97. HIGH THROUHGPUT SCREENING Automated microprocessor controlled robotic process HTS : 50000-100000 compounds can be screened per week against biological target u HTS : 10000-100000 compounds within 24hrs HTS assay system consist of sample wells for handling samples
  • 98. CHEMICAL LIBRARY  HTS ASSAYS  INFORMATICS AND ANALYSIS  PROCESS ENGINEERING
  • 99. MICROPLATE TECHNOLOGIES a.96 well microtiter plate 8 rows (A-H) 12 columns 88 test samples 8 controls b. 384 well microtiter plate 16 rows (A-P) 24 columns 352 test samples 32 controls
  • 100. c. 1536 well microtiter plate 32 rows ( A-AF) 48 columns 1,408 test samples 128 controls
  • 101. IN VITRO MARTIX – PHARMACODYNAMIC LIGAND STUDIES INTERACTION STUDIES PHARMACOKINETIC NATURAL PRODUCT STUDIES ISOLATION METABOLISM DRUG SYNTHESIS STUDIES
  • 102. Here an effective target is identified & validated for its function. HIT: it is a molecule with confirmed activity from primary hts assay,with good profile in 20 assays & with confirmed structure. LEAD: Lead is explained as a hit series for which SAR is studied.
  • 103. Fl.correlation spectroscopy Scintillation proximity Fl.anisotropy assay(SPA) Surface Fl.resonance sensitive energy fl.detection transfer Fl.life time imaging microscopy
  • 104. This procedure is suitable to detect receptor ligand binding reactions.
  • 106. The molecular interactions of drug & the receptor will give rise to measurable fluctuations in FI.
  • 107. When two different chromophores(drug & receptor) interact via dipole-dipole mechanism, transfers excitation energy non radially to acceptor chromophore.
  • 109. The sample is illuminated with pulsed laser & the life time of fl.probe is determined from the phase shift between the modulation of excitation light & emission of flourescence. Eg: measurement of tyrosine kinase activity.
  • 111. The membrane receptor can be immobilised using affinity tags Thus flourescence labelled ligand binds with it then the receptor emits fluorescence. Eg:flourescence antagonist on immobilized 5-HT3a receptor.
  • 112. An antibody or a receptor molecule, which is bound to a bead emits light when beta emission from an isotope occurs in close proximity; ie when a radiolabelled ligand binds to bead with receptor or antibody .
  • 115. Absorption studies: caco(colon cancer)cell line grow confluently & form a monolayer on polycarbonate support or collagen coated polycarbonate support. These are used for permeation studies.
  • 117. Due to development of 2-D multi parallel HPLC (SEPBOX,SEPIAtec,Germany) it is now possible to load up to 5g of NP extract & to isolate all compounds in 70-80% purity with in 24hrs.
  • 118. SEPBOX system works by using gradient elution & polarity based trapping in solid phase extraction(SPE). SEPBOX is coupled with photodiode array detector & light scattering detector in series enables the identification & quantification of the significant compounds. NP database containing about 10,000 structurally characterized natural compounds ,is being commercialized using MS & 2-D NMR.
  • 119. 1. Modern methods of drug discovery by A.Hillisch and R.Hilgenfeld page no: 72-98 2. Foye’s Medicinal chemistry by Thomas and David page no: 56-43 3. Medicinal chemistry by K.Illango page no: 389-407 4. http://www.sciencedirect.com/science 5. http://www.liebertonline.com/loi/adt 6. http://www.ingentaconnect.com/content 7. http://jbx.sagepub.com 8. http://www.nature.com/nmeth/index.html 9. http://mli.nih.gov/ 10. http://pubchem.ncbi.nlm.nih.gov/