TALK ON Drug

design
BY Indra Bhandari
  Introduction
DRUG is most commonly an organic small molecules that activates or inhibits the
function of a biomolecule such as a protein(receptor or enzyme) , which in turns
results in a therapeutic benefit to a patient.
DRUG DESIGN is an inventive process of finding new medications based on the
knowledge of a biological target.
Development of drugs from
Animals , plants, marine sources
The practical problems is faced in Drug discovery that the biological activity is not
properly correlated with the drug structure and related parameters .
In the basic sense , drug design involves the design of a small molecules that are
complementary in shape and charge to the biomolecular target with which they
interact and then drug will bind to it properly .
The Drug design implies random evaluation of synthetics as well as natural
products , creation of newer drug molecules based on biologically active
prototype derived from plant or animal i.e. LEAD COMPOUND
Drug design frequently relies on computer modeling techniques , this types of
modeling is often referred to as CAAD.
Drug design that relies on the knowledge of the 3-D structure of the
biomolecular target is known as structure based drug design

Drug discovery : it is an effort to produce new drug molecules from a lead

compound by applying variety of approaches of design . Drug design approach
is the prerequisite for drug discovery
Drug development: it is the process of establishing and marketing a
biologically active compound obtained by drug design , as a suitable drug by
observing ADME , toxicological and clinical parametres
 Stages required in drug discovery and drug
development
Choose a disease
Choose a drug target
Identify a bioassay
Find a lead compound
Isolate and purify the lead compound
Determine the structure of the lead compounds
Identify the SAR
Identify the pharmacophore
Improve target interaction
Improve PK and PD properties
Design a manufacture process
Carry out clinical trails
Market the drug
• The drug discovery and development of a new drug can take 10 years
or more , involve the synthesis of thousands compound and process
become expensive
• Drug design can be achieved by exploration (search of new molecules)
and exploitation(assessment , chemical modelling and extension ) of
lead compound
E.g
• Lead compound from natural source : morphine from opium
• Sulphanilamide isolated from the degradation of prontosil or synthesis
chemically
Natural source or synthetics source ---exploration and exploitation---
target binding ---biological activity
  Types of drug design
i. Ligand- based drug design
ii. Structure – based drug design

Ligand-based drug design (or indirect drug

design) relies on knowledge of other molecules
that bind to the biological target of interest .
• It is an important computational strategy in drug designing when
there is no macromolecular target structure present.
• In this method from a set 3D structures of known ligands, common
chemical features are procured.
• It involves two steps:
Finding the conformational flexibility of ligands
Finding common chemical features to develop pharmacophore
model
Steps
1. Pharmacophore identification
2. Pharmacophore modification
3. fit for the target receptor
4. Potential drugs
Structure-based drug design (or direct drug
design) : it relies on knowledge of the three
dimensional structure of the biological
target obtained through methods such as x-
ray crystallography or NMR spectroscopy
 In structure based drug design, new ligand is first
identified from large data bases with exact fitting with
receptor
Next the new ligand are assembled by suitable
selective of the small fragments of ligand.
Finally the molecule structure is optimized with exact
binding pocket
 Steps involved in structure based
drug design
Examination of the 3d structure of the
biological target (by x ray , NMR structure)
 Identification of active sites
Evaluation of structures
Synthesis of drug candidates
Biological screening
Lead compound discovery
  Introduction of RDD:

• Rational drug design is a focused approach that uses greater

knowledge about the drug receptor( target) i.e structural
information or one of its natural ligands as a design , identify
a lead .
Eg :
Librium is the first benzodiazepine , was further exploited to
developed potent analogue as diazepam (10X-potent)
 Different approaches used in drug
design
i. Approach with quantum mechanics ,
ii. Approach with molecular orbital theory ,
iii. Approach with molecular connectivity
and
iv. Approach with linear free- energy
 1. Approach with quantum mechanics

Quantum mechanics defines the behavior of proton , neutron and

electrons
 It also explains the molecular interactions in terms of distribution and
motion.
It is necessary to describe the quantized energy levels and to understand
the bonding electronic orbitals of atoms and molecules.
 It is also used in the electrostatic potential energy evaluation directly
Quantum mechanics (by Erwin Schrodinger in 1926 ) is an important
technique for "Drug design".
Erwin Schrodinger worked out mathematical expressions to describe the
motion of an electron in terms of its energy.
Quantum mechanics plays a vital role in CADD. It explicity deals with
proton, neutron and electron.
QM facilitates the drug to design by two means i.e. Structure based drug
design and ligand based drug design
 2. APPROACH WITH MOLECULAR ORBITAL
THEORY
This approach depicts the change in properties that shall be made by
the alteration of orbits.
Based on this, the electrons present in the molecules are linked with
orbitals to change the electronic feature.
The molecular orbital approach is the change on electronic charges,
evidenced from the investigation of three volatile inhalation
anaesthetics , On molecular conformation, as studied with respect to
acetylcholine, in regard to bond lengths and angles including
torsional angles.
These interpretations are carried out by computational methods in
respect to structure activity relationship (SAR)
 3.APPROACH WITH MOLECULAR
CONNECTIVITY
This is based on the structural features of a molecule. All steric
and electronic parameters varies according to their
configuration.
These includes cyclization, unsaturation, presence of
heteroatom, skeletal branching, and position in molecules with
the aid of numerical indices and the series of functional
attachments
 4.APPROACH OF LINEAR FREE-ENERGY
Linear free energy approach was based on the selection of
physiochemical parameters of a molecule with a specific biological
activity.
 But the biological activity may vary in relation to the physiochemical
properties of the drug or molecule
It does not provide a prompt success, but it may reveal some
beneficial features regarding the molecule.
Linear free energy relationship (LFER) was applied by Hammett to
predict the influence of substituents in the aromatic ring on the
reaction rates.
The LFER is useful to correlate the biological activity with LFER
changes in drug molecules.
THANK YOU
  DISCUSSION ON PRODRUGS
Prodrugs are bio-reversible derivatives of drug molecules that undergo an enzymatic
and/or chemical transformation in vivo to release the active parent drug, which can then
exert the desired pharmacologic effect.
• In both drug discovery and development, prodrugs have become an established tool for
improving physiochemical, biopharmaceutical, or pharmacokinetic properties of
pharmacologically active agents.
• The rationale behind the use of a prodrug is generally to optimize the ADME processes.
•Prodrugs are usually designed to improve oral bioavailability due to poor absorption from the
gastrointestinal tract. A few examples of blockbuster prodrugs are omeprazole, simvastatin,
lovastatin, enalapril, clopidogrel, valacyclovir, acyclovir, and oseltamivir
•Prodrugs are now an established concept to overcome barriers to a drug’s usefulness. About
5% to 7% of drugs approved worldwide can be classified as prodrugs
 Type of Prodrugs
Depending on constitution , lipophilicity , and method of
bioactivation
Hard Prodrug: A hard prodrug is a biologically active compound with a high lipid solubility or high
water solubility having a long biologic half-life. Examples include cocaine and heroin.
Soft Prodrug: A soft drug is a biologically active compound that is bio-transformed in vivo in a
rapid and predictable manner into nontoxic moieties. Examples include insulin and adrenaline.
Carrier-Linked Prodrug: A carrier-linked prodrug is a compound that contains an active drug
linked to a carrier group that can be removed enzymatically. These prodrugs are generally esters or
amides
 such a prodrug would have greatly modified lipophilicity due to the attached carrier. The active drug
is realized by hydrolytic cleavage either chemically or enzymatically. The prodrug should be
biologically inactive. The chemical linkage between the parent drug and its promoiety must be
bioreversible.
 The carrier-linked prodrug is subdivided into a bipartite prodrug that is comprised
of one carrier attached to drug. A tripartite prodrug is carrier connected to a
linker i.e. connected to a drug.

Bioprecursors : Bioprecursors are inert molecules obtained by chemical

modification of the active drug but do not contain a carrier.
 Such a moiety has almost the same lipophilicity as the parent drug and is
bioactivated generally by enzymatic redox metabolism.

Mutual Prodrug: Two, usually synergistic, drugs are attached to each other.
A bipartite or tripartite prodrug is one in which the carrier is a synergistic drug
with the drug to which it is link.
  According to the functional group
Carboxylic acid and alcohols: Pro-drugs of carboxylic acid and alcohol functionalities can
be prepared by conversion to esters.
• The esters can be easily hydrolyzed by esterase enzymes (e.g. lipase, ester hydrolase, cholesterol
esterase, acetyl cholinesterase, and carboxy peptidase) present in plasma and other tissues to
give active drug.
Eg: drug-coo-promoity + esterase ------drug-cooH +OH-promoiety

Amines: Due to the high stablility and lack of amidase enzyme necessary for hydrolysis, the
conversion of amines to amide as a pro-drug is not been used for most of the drugs. A more
common approach adopted is to use Mannich bases as pro-drug form of amines. example ;
• Hetacillin is a pro-drug form of ampicillin in which amide nitrogen and α amino functionalities
have been allowed to react with acetone to give a Mannich base (imidazolidine ring system). This
leads to decrease in the basicity and increase in the lipophilicity and absorption.
• Eg: ampicillin + acetone ----------------hetacillin
Azo linkage: Pro-drugs of amines are occasionally prepared by incorporating
them in to an azo linkage. By the action of azo reductase the amino compounds
are released in vivo.
E.g : Prontosil drug is inactive in vitro, but it is active in vivo since it is converted
to sulphanilamide by azo reductase enzymes

Carbonyl moiety: Conversion of carbonyl functionalities, such as aldehyde

and ketone, to pro-drug have not been found wide clinical use.
• They are converted into derivatives in which the sp2 carbonyl carbon is converted
as sp3 hybridized carbon attached to hetero-atoms. These pro-drugs are re-
converted to carbonyl compound by hydrolysis.
• For example, hexamine releases formaldehyde in the urine (acidic PH), which acts
as an antibacterial agent
  APPLICATIONS OF PRO-DRUG

The aim of pro-drug development is, in most cases, to solve specific pharmaceutic
or pharmacological and pharmacokinetic problems. The main objectives of pro-
drug are
o Improvement of taste. Two approaches are adopted to overcome the bad
taste of drug. The first is reduction of drug solubility in saliva and the other is to
lower the affinity of drug towards taste receptors, thus, masking the bitterness
Example : Parent drug(Chloramphenicol)---- Pro-drug with improved
taste(Palmitate ester )
oImprovement of odour. The odour of a compound depends on its vapour
pressure; a liquid with high v.p. will have a strong odour.
Example: ethyl mercaptan is a foul smelling liquid used in the treatment of
leprosy. This is converted to phthalate ester
  APPLICATIONS OF PRO-DRUG
o Enhancement of bioavailability. Altering the polarity of the ampicillin ,
by esterifying the free carboxyl group results in compounds that are completely
absorbed, that is, with greater bio-availability than the parent ampicillin.
o Improvement of stability and solubility properties.
o Decreased toxicity and adverse reactions.
o Increased site specificity.
o Increased duration of pharmacological actions.
o Drug absorption, distribution, metabolism, and excretion
affect pharmacokinectis.
THANK YOU
  INTRODUCTION OF QSAR
• The identification of a new drug molecule requires a lot of synthesis,
time and money.
• It was identified that out of billion molecules synthesized, around one
or two molecules reach the clinical trials. This produces hurdle in the
discovery new chemical entities (NCEs) for the treatment of various
diseases.
• The quantitative structure activity relationship approach has proved
extremely useful in tackling this problem.
1. QSAR is a mathematical relationship between a biological activity of
a molecular system and its geometric and chemical characteristics.
2. QSAR attempts to find consistent relationship between biological
activity and molecular properties, so that these "rules" can be used
to evaluate the activity of new compounds.
• QSAR approach attempts to identify and quantify the physicochemical
properties of a drug and to see whether any of these properties has an
effect on the drug's biological activity.
• QSAR involves the derivation of mathematical formula or equation which
relates the biological activities of a group of compounds to their
measurable physicochemical parameters. These parameters have major
influence on the drug's activity.
• QSAR derived equation take the general form:
Biological activity = function (parameters)
• Activity is expressed as log(1/C). C is the minimum concentration
required to cause a defined biological response.
• The QSAR equation is developed by considering the physiochemical
properties contributing to biological activity.
• THE QSAR EQUATION WILL PREDICTTHE BIOLOGICAL ACTIVITY FOR THE
NEW MOLECULES TO BE DESIGNED.
• The QSAR equation derived is:
log(activity)=Ycalc= kıX + k2
It is measure of how well the equation explains the
v’ariance in activity observed in terms of
physicochemical parameters present in the equation.
• Ycalc = log(observed activity)
• X=physicochemical property
• K1& k2= rate constant
Various parameters used in OSAR
studies
Hydrophobicity: partition coefficient (log P),
Hansch's substitution constant i.e - substitution
constant
Steric Parameters: Taft's constant Es
Electronic Parameter: Hammet`s constant ,
lonization constant; pKa,
 Hydrophobicity (log P Partition Coefficient)
• Hydrophobicity (log P Partition Coefficient): Lipid is an vital
constituent of the cell membrane, the hydrophobicity of drug is an
important parameter plays a vital role from drug administration,
distribution and interaction with receptor or target site to produce
the biological response.
• The optimum hydrophobicity is required to transport the drug to the
site of action.
• Hydrophobicity of a drug is measured experimentally by testing the
drugs relative distribution is known as partition coefficient
• Partition coefficient: Partition coefficient p usually expressed as log
P. This is generally found by ideal solvent n- octanol and water
(aqueous)
• It is defined as p=C octanol / C aqueous
• In simpler term the partition coefficient is the ratio of drug in n-
octanol and water
• The n- octanol solvent will mimic the lipid compartment in the
body and water will mimic aqueous compartment of the body. P
is generally expressed as log P because it depends upon various
functional groups plus the whole molecule.
• The whole organic molecule comprised of basic skeleton plus
various substituents. The contribution of hydrophobicity by
substituents is expressed as pie and sum of is equal to logP.
logP=
=hydrophobic substituent constant
LogP = [drug] in octanol / [drug] in water
Biological activity normally expressed as 1/C,
where C=[drug] required to achieve a defined level of biological
activity.
The more active drugs require lower concentration.
Plot log 1/C vs. log P
Typically over a small range of log P, a straight line is obtained
log 1/C= k1 log P + k2
 ELECTRONIC PARAMETER
• The electronic effect of various substituent will clearly have an effect
on drug ionization and polarity.
• Have an effect on how easily drug can pass through the cell
membrane or how strongly it can interact with a binding site.
• The distribution of electron in the molecule influences the activity of
drug molecule. The drug should cross the various barriers to reach
the site of action to produce the biological response.
• Generally unionized molecules are easily transported across the
membrane than the ionized molecules.
• The reason behind the ionized and charged molecules are opposed
by the electrical charge present in membrane unwind
• Neutral molecules have no charge so that their transport across the
membrane is facilitated easily without any electrical interruption.
 Hammett Constant(
• values are the logarithm of the effect of the substituent on the acid
dissociation constant of benzoic acid
=log (Kx/K)
=log Kx -log K
K=Equilibrium constant for parent compound (benzoic acid)
Kx= equilibrium constant for substituted benzoic acid
• This is a measure of the electron-withdrawing or electron-donating ability
of a substituent. The arrangement of electron in a drug molecule depends
upon electron donors and acceptors.
• Electron withdrawing group, result in the aromatic ring having a stronger
and stabilizing influence on carboxylate anion. The equilibrium shift more
to ionized form such a larger kx value. (+ve value)
• If substituent X is an electron donating group such as alkyl, then aromatic
ring less able to Stabilize the carboxylate ion. EquiIibrium shifts to left and
smaller kx value. (-ve Value)
 Taft's steric factor (Es)
• The shape and size of the molecules are very important for a drug to
bind on its active site.
• A small substituents may facilitate the molecule to interact with the
receptor freely whereas bulky group may offer the hindrance.
• However sometime bulky substituents may orient the molecule to
receptor effectively .
• The hydrophobic and electronic parameters are easy to quantify but
it is difficult to measure the steric property. In order to solve the
complexity in Hammett equation 1952 Robert W. Taft modified the
Hammett equation to quantify the steric contribution by taking the
acid hydrolysis to alpha substituted methyl ethanoates. i.e esters
• The reason to take this molecule is that the steric property controls
the hydrolysis.
 Substituent H F Me Et

Es 1.24 0.78 0 -0.07

• For example: reference ester is X=Me

• Substituent H n F smaller than Me result in faster hydrolysis, Es = +ve
• Substituent larger than Me reduce rate of hydrolysis, Es = -ve
 HANSCH ANALYSIS OR EQUATION
• For the past few decades, scientist used a random drug discovery
process which takes 15-20yrs to develop a drug candidate with huge
expenditure along with high manpower. But now a day the drug
discovery process is advanced by adopting several scientific and
mathematical logic.
• The rational drug discovery approach adopts various parameters to
predict the biological responses with the available literature such as
physicochemical properties.
• The rational drug design has the predictive power and this increases
with respect to the member of the physicochemical parameter
added.
• The discipline of QSAR was initiated by Prof Corwin Hansch in 1962, he
laid the foundation of QSAR by three important contributions :
1- Combination of several physicochemical parameters in one regression
equation.
2-Definition of lipophilic parameter
3- Formulation of the parabolic model for nonlinear lipophilicity-
bioactivity relationship.
• Hansch proposed an approach which mainly deals with the lipophilicity
including steric and electronic parameters.
• As per Hansch, the drug action is elicited by two steps:
a) Transport of drug to the site of action
b) Binding of the drug to the target site to produce biological response
• The drug under go 'random walk' from the point of administration to its
site of action. During this process the drug passes various barriers which
signifies the involvement of lipophilicity.
• Rate of biological response=d (response)/AC kx
A= probability of the drug to reach the site of action ,C= drug
concentration and Kx=Rate constant
• Based on this , Hansch postulated simple mathematical relationship as:
Log (1/C) = k1 (partition parameter) + k2 (Electrical parameter) + k3
(steric parameter)
Log (1/C) = k1 Log P + k2 + k3 Es....Hansch equation
Where C is the minimum concentration of drug and k1, k2 and k3 are
constant.
The numerical values of the constants and these parameter values are
obtained either from the literature or determined by experiment.
Thank you
 INTRODUCTION :Pharmacophore
• Pharmacophore concept was proposed by Paul Ehrlich in 1909.
pharmacophore is defined as 'a molecule framework that caries the
vital features required for biological activity of a drug’
• IUPAC defines a pharmacophore to be "an ensemble of steric and
electronic features that is necessary to ensure the optimal
supramolecular interactions with a specific biological target and to
trigger (or block) its biological response".
• Pharmacophore model is used to express the 2D and 3D image of
the molecule and to depict the key elements necessary for binding.
• This concept is generally used for binding, to identify the target,
virtual screening, molecular docking simulation etc.
• A pharmacophore model explains how structurally diverse ligands
can bind to a common receptor site
• Pharmacophore approaches are successful subfields of CADD which have
become one of the major tools in hit identification , lead optimization , and
rational design of novel drugs .
• A pharmacophore represents molecules features including as :
i. 1D( physical or biological properties )
ii. 2D(substructures)
iii. 3D(hydrophobic group , charged/ionizable group , H donor or acceptor)
• Typical pharmacophore features include hydrophobic centroids , aromatic
rings , hydrogen bond acceptors or donors , cations , and anions .
• These pharmacophoric points may be located on the ligand itself or may be
projected points presumed to be located in the receptor.
• The features need to match different chemical groups with similar
properties , in order to identify novel ligands.
Types of pharmacophore modelling
Structure based pharmacophore modelling
(DDD)
Ligand based pharmacophore modelling (IDD)
 STRUCTURE BASED PHARMACOPHORE MODELLING
(DIRECT DRUG DESIGN)
• The structure-based pharmacophore modeling generates chemical
features of the active site and the sterical relationships from 3D
structure of macromolecular target or macromolecule-ligand complex.
lt probes the possible interaction sites between the macromolecular
target and the ligands.
• Here structure refers 3D structure of protein or receptor structure. The
nut and bolt of the 3D structure of the receptor/protein/target site is
analysed , hydrophobic part or the hydrophilic part are studied and
analyzed to get the information needed for drug design.
• Drawback: the methods fails when the information about target site is
unknown The various binding pocket/ cavity of the receptor,
 LIGAND-BASED PHARMACOPHORE MODELLING
(INDIRECT DRUG DESIGN)
• Ligand-based drug design (or indirect drug design) relies on knowledge of other
molecules that bind to the biological target of interest. It is an important
computational strategy in drug designing when there is no macromolecular target
structure present. In this method, from a set 3D structures of known ligands, common
chemical features are procured.
• It involves two steps:
• a. Finding the conformational flexibility of ligands
• b. Finding common chemical features to develop pharmacophore model
• In the absence of the macromolecular target structure, ligand-based pharmacophore
modeling is an essential strategy for drug discovery.
• In this method, the common chemical characteristics from 3D structures of multiple
known ligands are extracted through ligand alignment, which would represent the
essential interactions between ligand and potential macromolecular target.
 MOLECULAR DOCKING
• Docking is the structural – based technique which attempts to find the best
match , between the two molecules .
• In the field of molecular modeling, docking is a method which predicts
the preferred orientation of one molecule to a second when bound to
each other to form a stable complex.
• Knowledge of the preferred orientation in turn may be used to predict
the strength of association or binding affinity between two molecules
using for example scoring functions.
• It is a computational procedure to find out the active ligand which can
bind with target site effectively. The molecular docking studies are useful
to find out the lead compound which can fit in to receptor effectively.
• The docking studies give reliable information about the perfect
orientation of ligand with protein and to use same in rational drug
design.
MOLECULAR DOCKING
 Types of Molecular docking
1- Lock and key Docking (Rigid docks)
2-Induced fit docking (flexible docking)
In rigid docking geometry of the ligand and receptor is
kept constant.
In flexible docking, receptor and ligand are kept flexible
and the associated energy is calculated, this method is
good to study about binding patterns of the drug with
receptor.
MOD: structure of the protein of interest( x-ray, NMR
spectroscopy and homology modeling construction).
The success of a docking program depends on two
components ;
a. Search algorithm : determine possible orientation
Common software used for docking purpose
• UCSF DOCK – USA
• AUTODOCK- USA
• GOLD – UK
• FlexX –GERMANY
• OTHERS
Virtual screening
 DE NOVO DRUG DESIGN
• It is a process in which the 3D structure of the receptor is used to design
the newer molecules .
• It involves the structure determination of the lead target complexes and
design of lead modification using molecular modeling tools
• When the satisfactory ligand could not be screened through virtual
screening
• ADME profile is not provided
• Ludi , sprout , etc
Protein structure
 Binding site
• Binding site identification :It is the first step in structure based
design.
• Relies on identification of concave surfaces on the protein that
can accommodate drug sized molecules that also possess
appropriate "hot spots" (hydrophobic surfaces, hydrogen H-H-
H-bonding sites, etc.) that drive ligand binding.
CADD ( COMPUTER AIDED DRUG DESIGN)
 INTRODUCTION COMBINATORIAL CHEMISTRY
It is a novel synthetic chemistry which enables the medicinal chemistry
to synthesize large number of chemical compounds (chemical library).
The primary objective of this advanced medicinal chemistry is to reduce
the cost and time of the drug discovery. The impressive outbreak in
combinatorial chemistry was given by Robert Bruce Merrifield for the
invention of solid phase peptide synthesis in 1963.
combinatorial chemistry (COMBICHEM) is a collection of techniques
which allow for the synthesis of multiple compounds at the same time.
this powerful new technology has begun to help pharmaceutical
companies to find new drug candidates quickly, save significant money
in preclinical development costs and ultimately change their
fundamental approach to drug discovery.
 DEFINITION OF COMBINATORIAL CHEMISTRY
• It is a technique by which large numbers of different but structurally similar
molecules are produced rapidly and submitted for pharmacological assay
• This technique uses the same reaction conditions with the same reaction
vessels to produce a large range of analogues
• In combinatorial chemistry, large numbers of compounds are made at the
same time in small amounts, forming libraries which can be assayed for
desired properties all at once.
• Finally the active compound is identified and made in quantity as a single
compound
• Combinatorial chemistry encompasses many strategies and processes for the
rapid synthesis of large, organized collections of compounds called libraries.
• The collection is then tested for the biological activity , finally the active
compound is identified and made in quantity as a single compound.
Thus the combinatorial chemistry approach has two phases
1.Making a library( collection of compound )
2.Finding the active compound
In the past, chemists have traditionally made one compound at a time. For
Example compound A would have been reacted with compound B to give
Product AB which would have been isolated after reaction work up and
Purification through crystallization, distillation or chromatography.
 PRINCIPLE OF COMBICHEM
• To prepare a large number of different compounds at the same
time instead of synthesizing compounds in a conventional one
at a time manner and then to identify the most promising
compound for further development by high throughput
screening (HTS).
• In combinatorial synthesis different compounds are generated
simultaneously under identical reaction conditions in a
systematic manner, so that ideally the products of all possible
combinations of a given set of starting materials (termed
building blocks) will be obtained at once.
• The collection of these finally synthesized compounds is
referred to as a combinatorial library, the library is then
screened for useful properties and the active compounds are
identified.
 NEED FOR COMBINATORIAL CHEMISTRY
 Problems with traditional /conventional synthesis
• 1 chemist 1 molecule :can only make one molecule at a time
• Each synthesis is very time consuming :Multistep synthesis have loss
at each step and purification of products very time-consuming
between steps.
• Yields can be low and produces very few molecules at a time for
testing.
• Slower lead generation: hundreds of molecules in a month are
generated
• HIGH RISK OF FAILURE.
 BENEFITS WITH COMBINATORIAL SYNTHESIS

• 1 chemist-multiple molecules :Can make multiple molecules at a time.

• The time & cost associated with the generation & analysis of each
individual molecule is significantly less when compared to the time &
cost of an Individual synthesis
• Yields can be high and produces many molecules at a time for testing.
• Faster lead generation.
• Thousands of molecules in a month are generated
• Low RISK OF FAILURE.
• A multiple molecules synthesized at a time.
 APPLICATIONS OF COMBINATORIAL
CHEMISTRY
• Applications of combinatorial chemistry are very wide ,
scientists use combinatorial chemistry to create large
populations of molecules that can be screened efficiently.
• By producing larger, more diverse compound libraries,
companies increase the probability that they will find
novel compounds of significant therapeutic and
commercial value.
• Provides a stimulus for robot-controlled and
immobilization strategies that allow high-throughput and
multiple parallel approaches to drug discovery
 ADVANTAGES

• Fast : Combinatorial approach can give rise to million of compound in same time
as it will take to produce one compound by traditional method of synthesis
• Economical
• Easy : Isolation , purification & identification of active molecule from
combinatorial library is relatively easy.
• Drug discovery
i. Mixed combinatorial synthesis produces chemical pool
ii. Probability of finding a molecule in a random screening process is proportional
to the number of molecules subjected to the screening process
• Drug optimization : Parallel synthesis produces analogues with slight differences
which is required for lead optimization
 TYPES OF COMBICHEM

COMBINATORIAL CHEMISTRY IS OF TWO TYPES:

• 1. SOLID PHASE COMBINATORIAL CHEMISTRY (compound library
synthesized on solid phase such as resin bead)

• 2. SOLUTION PHASE COMNATORIAL CHEMISTRY (compound library

synthesized in solvent in the reaction flask)
 SOLID PHASE COMBINATORIAL CHEMISTRY
• In solid phase combinatorial chemistry, the starting compound is attached to an
insoluble resin bead, reagents are added to the solution in excess
• The resulting products can be isolated by simple filtration, which traps the beads
while the excess reagent is washed away
STEPS
• attach the starting molecule to an inert solid/resin bead.
• addition of excess of reagents to the solution.
• separation of products (attached to resin beads) by simple filtration.
• cleavage & isolation of products from the beads.

 REQUIREMENTS: solid support (resin beads) , an anchor or linker , a bond

linking the substrate to the linker , a means of cleaving the product from the
linker at the end and protecting groups
  Examples of solid supports
• Partially cross-linked polystyrene beads: polystyrene is cross linked
with divinyl benzene, hydrophobic in nature, causes problems in
peptide synthesis due to peptide folding.
• Sheppard's polyamide resin - more polar
• Tentagel resin - similar environment to ether
• Beads, pins and functionalised glass surfaces
Characteristics of solid support:
• Beads must be able to swell in the solvent used, and remain stable.
• Most reactions occur in the bead interior
 AN ANCHOR OR LINKER
• A molecular moiety which is covalently attached to the solid support, and which
contains a reactive functional group.
• Allows attachment of the first reactant.
• The link must be stable to the reaction conditions in the synthesis but easily
cleaved to release the final compound.
• Different linkers are available depending on the functional group to be attached
and the desired functional group on the product.
• Resins are named to define the linker
e.g Merrifield resin
wang resin
Rink amide resin
Photolabile anchors
Traceless anchors
 PROTECTING GROUPS
• A protecting group is reversibly attached to the functional group to convert
to a less reactive form.
• When the protection is no longer needed, the protecting group is cleaved
and the original functionality is restored.
• Protecting group to be stable under the expected reaction conditions and
to be cleavable if possible-at mild reaction conditions.
• Some of the protecting groups most widely used in peptide synthesis are:
i. Benzyl carbonyl (z) group
ii. T-butoxy carbonyl (BOC) group
iii. 9-fluorenyl methoxy carbonyl (FMOC) group
 ADVANTAGES OF SOLID PHASE SYNTHESIS
• Specific reactants can be bound to specific beads
• Beads can be mixed and reacted in the same reaction vessel
• Products formed are distinctive for each bead and physically distinct.
• Excess reagents can be used to drive reactions to completion .
• Excess reagents and by products are easily removed.
• Reaction intermediates are attached to bead and do not need to be isolated
and purified.
• Individual beads can be separated to isolate individual products.
• A polymeric support can be regenerated and reused after cleaving the
product.
• Automation is possible
 SOLUTION PHASE COMBINATORIAL CHEMISTRY
• The solution phase synthesis involves conducting chemical reaction simultaneously
preferably in well-ordered sets (arrays) of reaction vessels in solution , most ordinary
synthetic chemistry takes place in solution phase .
• The use of solution phase techniques has been explored as an alternative to solid-phase
chemistry approaches for the preparation of arrays of compounds in the drug discovery
process.
• Solution phase work is free from some of the constraints of solid-phase approaches but
has disadvantages with respect to purification.
• The main disadvantage of this method is when number of reagents are taken together in
a solution, it can result in several side reactions and may lead to polymerization giving a
tarry mass.
• Therefore, to avoid this, the new approach is developed in which all chemical structure
combinations are prepared separately, in parallel on a giving building block using an
automated robotic apparatus.
• For example: hundreds and thousands of vials are used to perform the reactions and
laboratory robots are programmed to deliver specific reagents to each vial.
• All chemical reactions are conducted simultaneously, preferably in
well- ordered sets (arrays) of reaction vessels in solution.
• Soluble polymer are used as support for the product
 limitation
• When numbers of reagents are taken together in a solution
i. It can result in several side reactions and
ii. Lead to polymerization giving a tarry mass.
COMPARISION BETWEEN SOLID PHASE AND SOLUTION
PHASE
 MOLECULAR MODELLING
• Molecular modelling allow scientists to use computers to visualize
molecules means representing molecular structures numerically and
simulating their behavior with the equations of quantum and
classical physics , to discover new lead compounds for drugs
• The term " Molecular modeling "expanded over the last decades
from a tool to visualize three-dimensional structures
• To simulate, predict and analyze the properties and the behavior of
the molecules on an atomic level to data mining and platform to
organize many compounds and their properties into database and to
perform virtual drug screening via 3D database screening for novel
drug compounds.
• Goal :To develop a sufficient accurate model of the system so that
physical experiment may not be necessary .
 ligand based design

• Chemical structure of Active compound / Lead / Hit

• Analogues with known Bioactivity

• QSAR . pharmacophore

• Lipinski's rule Drug Likeness property ADME

 3D structure unknow Know
Target based design
• ldentify target • ldentify target
• Primary sequence known
• Active site determination
• Compare with known target
proteins/enzymes • Binding studies with
• Homology modelling and ligand

• Obtain 3D structure
• Correlate Binding energy
• Correlate Binding energy & & activity
activity