Combinatorial Chemistry

Solid and solution phase chemistry

Traditional methods
• The traditional methods of drug design involves re synthesis of large
number of compounds and their biological testing in order not to
miss promising marketable products. However, these methods are
costly and sometimes there is waste of time and energy.
• Wet lab methods for the synthesis of peptides are very cumbersome,
and often optical purity is not achieved. Most of the times peptides
cannot be resolvable as they will be obtained as racemic compounds
This is one of the major limitations of peptide synthesis from wet lab
method, which can be overcome by using combinatorial chemistry.
Combinatorial chemistry and its applications
• Combinatorial chemistry was introduced in mid eighties and several
reports are available on the new leads from combinatorial libraries.
UGI is regarded as father of combinatorial chemistry , he used Multi
component reaction in 1962 to explain this concept. Merrifield solid
phase chemistry in 1963 offered necessary tools.
From 1990 onwards small molecules were synthesized from multiple
component mixture , since then combinatorial libraries has expanded
from peptides to organic, organometalic, inorganic and polymer
chemistry and its industrial applications have spread from pharma
industry to other industry such as catalyst, polymers, advanced
materials, pigment and agro chemicals
Principle of Combinatorial chemistry
• Combinatorial chemistry synthetic methods allow the rapid synthesis
of large number of candidate molecules with the desired chemical
structural features called as Scaffold as well as a variety of other
ancillary chemical structural features.
• It is a technique by which large number of structurally distinct
molecules will be synthesized in a time and resource effective
manner and then will be submitted for pharmacological assay in
variety of forms. A range of analogues can be produced using similar
reaction conditions either in same reaction vessel or individually in
parallel using semi automated synthesis
New Drug Discovery program
• Identification of biological targets and their validation
• Lead discovery –lead modification- lead validation
• Lead Optimisation
• Selection of drugs
• Combinatorial chemistry plays a major role and has impact in lead
discovery and lead optimization.
It is one of the effective process in lead optimisation than lead
discovery
 Solid phase chemistry
• used to simultaneously create compounds and screen for analysis. It is
based on the work of Merry field. This method was used for the production of
peptide. Each of the key reaction has been optimized to allow the production
of peptides of sizable length with overall good yield.
1.A cross linked insoluble polymer material that is inert to the conditions of the
reaction.
2.Some means of linking the substrate to the solid phase that permits the
selective cleavage of some or all of the products from the solid support during
the synthesis for the analysis of the extent of thee reactions and finally to give
final products of interest.
3.A chemical protection strategy to allow the selective orthogonal protection
and deprotection of reactive groups in the manomers.
Other methods of solid phase synthesis
• Mixed reagent method: In this method combinatorial chemistry
libraries are prepared by using mixtures of amino acids in the
acylation steps. Disadvantages: 1:1 molar ratio is not obtained.

• Biological Method: Use of phage display libraries is there. The DNA of

the phage can be considered as an encoding tag. Here phage
resembles the bead in the portion mixing synthesis with each
containing an individual compound. Here sequence of peptide can be
determined by the sequencing of proper portion of DNA
• The light directed parallel chemical synthesis: This method is used to
prepare an array of peptides or other kind of molecules on the
surface of the glass slide. The surface of glass slide is functionalized
with amino alkyl groups protected with photo labile 6 nitro
veratratryloxy carbonyl groups. Amino acid synthesized in this is also
protected by these groups.
The important requirement for the solid phase synthesis
includes the following:
• Solid support: Merrifield resin, is a polystyrene resin derivetized with
a chloro methyl group
Sheppard’s resin is a polyamide resin
Parallel synthesis
• In this approach, all the chemical structures combinations are
prepared separately in parallel on a given chemical structures using
an automated robotic synthetic apparatus . Robots are programmed
to deliver specific reagents to each vial. This method is best suited for
the development of small chemical libraries. Different methods of
parallel synthesis is as follows:
• Multipin method
• Tea bag method and
• The spot technique.
Solution Phase synthesis
This utilizes polymer supported resin and the scavenger resin.
• Scavenger resins are used to remove excess reagents or reaction
byproducts after reaction is complete.

• Liqued phase portion mixing: Here synthesis is carried out on the poly
ethylene glycol mono methyl ether support. This polymer is soluble in
the course of the reaction and the homogenous phase is
advantageous for the coupling but can be precipitated allowing the
excess reagent to be wasted out.

• Deconvolution method: This method mainly helps to determine

which substance in the multi component combinatorial library has the
Applications of Combinatorial Chemistry
• It allows medicinal chemist to systematically produce large libraries of small drug
molecules together with high throughput screening.Combinatorial chemistry has
led to significant impact on pharma companies.
• The pro select technique combines the benefit of combinatorial chemistry and
structure based drug design
• The pro select approach has been used to create small libraries targeted against
the therapeutically important serine proteases trypsin and factor Xa.
• The important combinatorial synthesis are:
• Peptide and oligo nucleotides Eg HIV protease inhibitor
• Peptide and other amides Eg,identification of potent endothelin inhibitors as
innovative anti hypertensive drugs
• Heterocyclic synthesis Eg 1, 4 benzo diazepine derivatives, Tri substituted
piperazine diones , tetrahydro furans.