Drug Design, Discovery and Development

Drug design, sometimes referred to as rational drug design or more

simply rational design, is the inventive process of finding new medications
based on the knowledge of a biological target. The drug is most commonly
an organic small molecule that activates or inhibits the function of a
biomolecule such as a protein (receptor or enzyme), which in turn results in
a therapeutic benefit to the patient. In the most basic sense, drug design
involves the design of small molecules that are complementary in shape
and charge to the biomolecular target with which they interact and therefore
will bind to it.

What is really meant by drug design is ligand design (i.e., design of a small
molecule that will bind tightly to its target). Although modeling techniques for
prediction of binding affinity are reasonably successful, there are many
other properties, such as bioavailability, metabolic half-life, lack of side
effects, etc., that first must be optimized before a ligand can become a safe
and efficacious drug.
 The ‘drug design’ in a broader sense implies random
evaluation of synthetic as well as natural products in
bioassay systems, creation of newer drug molecules
based on biologically-active-prototypes derived from
either plant or animal kingdom (lead compound),
synthesis of congeners displaying interesting biological
actions by different approaches of molecular
modifications and finally precise design of a drug to
enable it to interact with a receptor site efficaciously.
 Drug design frequently but not necessarily relies on
computer modeling techniques. This type of modeling is
often referred to as computer-aided drug design.
Finally, drug design that relies on the knowledge of the
three-dimensional 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: Drug development is the

process of establishing and marketing a biologically
active compound obtained by drug design, as a
suitable drug by observing pharmacokinetic (ADME),
toxicological and clinical parameters.
 Stages required in drug discovery and drug
development

 Drug design and drug discovery

 Choose a disease
 Choose a drug target
 Identify a bioassay
 Find a ‘lead compound’
 Isolate and purify the lead compound if necessary
 Determine the structure of the lead compound
 Identify structure-activity relationships (SARs)
 Identify the pharmacophore
 Improve target interactions
Drug Development

 Improve pharmacokinetic properties (ADME)

 Toxicological evaluation
 Design a manufacturing process
 Carry out clinical trials
 Market the drug
 Make money!

 The discovery and development of a new drug can

take 10 years or more, involve the synthesis of over
10,000 compounds and cost in the region of $360
million.
 Lead Compound

 It is a chemical compound obtained from natural or

synthetic sources that possesses a particular
biological activity.

 A lead can be characterized as a compound that has

some desirable biological activity, not extremely polar
or lipophilic, and not contain toxic or reactive
functional groups. Often, molecular weight (<350) and
lipophilicity (log P<3) are considered the most
obvious characteristics of a drug-like lead.

 The lead should also have a series of congeners that

modulate biological activity, indicating that further
structural modification will improve selectivity and
potency.
 Drug design can be achieved by exploration of the
lead compounds, which involves the search for a
new lead or exploitation of the existing leads to
produce more active compounds with less toxicity
than the original lead compound.

 Example:
 i. Sulphanilamide- isolated from the degradation of prontosil or
synthesized chemically and acts as antibacterial agent.
 ii. Lead compound from natural sources: Morphine from opium,
cocaine from coca leaves, and quinine from the bark of
cinchona tree.
 Objective / Aim of drug design strategy

 To improve the activity and properties of the lead

compound.
 To improve the binding interactions between a drug
and its target, which will increase activity and may
also reduce side effects if the improved interactions
lead to increased selectivity between different
targets.

Principal drug targets: i. Receptor ii. Enzyme iii.

Nucleic acid
 TRADITIONAL DRUG DESIGN
(Pharmacophore-based drug design)

Lead generation:
Natural ligand / Screening

Biological Testing

Drug Design Cycle

If promising
Synthesis of New Compounds by
molecular modification of leads
Pre-Clinical Studies
 Structure-based Drug Design (SBDD) or
Target-based approach

Natural ligand / Screening

Molecular Biology & Protein Chemistry

3D Structure Determination of Target

and Target-Ligand Complex
Modelling

Drug Design Cycle

Structure Analysis
Biological Testing
and Compound Design
If promising

Synthesis of New Compounds

Pre-Clinical
Studies
 A pharmacophore was first defined by Paul Ehrlich in 1909 as "a
molecular framework that carries (phoros) the essential features
responsible for a drug’s (=pharmacon's) biological activity“.

In 1977, this definition was updated by Peter Gund to "a set of

structural features in a molecule that is recognized at a receptor site
and is responsible for that molecule's biological activity“.

The IUPAC definition of a pharmacophore is "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-based drug design

 1. Determine identity of a “lead compound”:

 Screen natural and synthetic banks of

compounds for activity
 Folk medicine
 Natural ligand
 Drug already known
 Computer-aided drug design
 Computerized search of structural databases
2. Data collection: Publications; patents; biological
activity; NMR and X-ray data; physiochemical
properties to determine the effects of structural
changes on activity of drug: structure-activity
relationships (SARs)

3. Analysis: integrate information about drug (and

target) to generate hypothesis about activity. This
information will result in the identification of a
pharmacophore…
Pharmacophore-Based Drug Design: Methods

Four Methods used to design better drugs:

 Chemical modification / Molecular modification

 Database searching

 De novo (from the beginning) approach

 Manual

These approaches generate more data, which yet

again can be used to generate new hypotheses
and structures, etc.
 Design method: Chemical modification

 Goal: Determine Structure- activity relationships to know what

functional groups are important to biological activity.

Procedure: Alter or remove groups using chemical synthesis

and test the activity of the altered molecule (analog). Infer role
of those groups in binding.

 Consequences of chemical modification to drug activity in

addition to altering binding interactions:

 metabolism of drug
 pharmacokinetics
 Molecular modification of lead compound:
Formation of Analogues and Prodrugs

 Drug design is usually achieved through molecular

modification of the lead compound. In the course of drug
design the two major types of chemical modifications are
achieved through the formation of analogues and prodrugs.

 An analogue is normally accepted as being that modification

which brings about a carbon-skeletal transformation or
substituent synthesis. Examples: oxytetracycline,
demclocycline, chlortetracycline.
Examples of drug design through the formation of analogues

OH O OH O O
OH
1 NH2
8 6 5
7 OH
H3C OHH H N(CH3)2

Tetracycline
Activity: against wide range of gram-positive and gram-negative bacteria
including rickettsia, Mycoplasma etc.

OH O OH O O
OH O OH O O OH
OH
NH2
NH2
OH
OH
Cl H OH N(CH3)2
ClH3C OH N(CH3)2
Chortetracycline Demeclocycline

OH O OH O O
OH
NH2
OH
H3C OHOH N(CH3)2

Oxytetracycline
 The term prodrug is applied to either an appropriate
derivative of a drug that undergoes in vivo
hydrolysis of the parent drug, e.g., testosterone
propionate, chloramphenicol palmitate and the like;
or an analogue which is metabolically transformed
to a biologically active drug, for instance:
phenylbutazone undergoes in vivo hydroxylation to
oxyphenylbutazone.
 O
N

N
n-C4H9

OH
O

Oxyphenylbutazone

(Better tolerated than

phenylbutazone)
O
N

N
n-C4H9

O
Phenylbutazone N

Antirheumatic drug H3C HCH2CH2C N

HO O

Phenylbutazone alcohol

(uricosuric agent)
 Serendipitous drug discovery
 "Serendipity" in drug discovery implies the finding of one
thing while looking for something else i.e. accidental
discovery or discovery by chance.

The discovery of penicillin's and sulfonamides as the

antibiotics and antibacterial agents respectively are the
suitable examples serendipitous drug discovery.
Examples of Drug design through serendipity : Sulphonamides or Sulfa
Drugs
Activity: Antibacterial especially against some common gram-positive bacterial infections.
Diseases like pneumonia, meningitis, dysentery etc. acting as powerful bactericides.

(4) (1)
H2N SO2NH2

Lead compound: p-aminobenzenesulphonamide, known as sulphanilamide

Sulphanilamide: first synthesized by Gelmo in 1908 as an intermediate in the study of azo dyes.
Therapeutic value was ascertained by Gerhard Domagk (German scientist) in 1935. Found active
against streptococci.
NH2
H2N SO2NH2 NaNO2/HCl
ClN N SO2NH2 H2N NH2
10 0C
Sulphanilamide
Diazotized sulphanilamide P-aminophenyldiamine

NH2
Reduction
H2N SO2NH2 H2N N N SO2NH2

Sulphanilamide (in vivo)

Prontosil

N
H2N SO2NH
N H2N SO2NH
N
Sulphpyridine: more potent than
sulphanilamide for the treatment Sulphadiazine: dysentery, pneumonia.
of pneumonia but more toxic.

CH3
S
H2N SO2NH H2N SO2NH O
N N
Sulphathiazole: very effective in Sulfamethoxazole: UTI, RTI, GI infections.
staphylococcal infections.
Serendipitous Discovery of Chlordiazepoxide (Librium)
without a Lead

 In 1955 Roche set out to prepare a series of

benzheptoxadiazines as potential new tranquilizer drugs, but
the actual structure was found to be that of a quinazoline 3-
oxide.

R1 N R1
N
O X N+ -
X O
N
Y R2
Y R2
2.5
2. 4

No active compounds were found, so the project was abandoned.

In 1957, during a lab cleanup, a vial containing what was thought
to be the latter compound (X = 7-Cl, R1 = CH2NHCH3, R2 = C6H5)
was sent for testing, and it was highly active.
Further analysis showed that the actual structure of the
compound was the benzodiazepine 4-oxide (chlordiazepoxide
HCl), Librium (the first benzodiazepine) presumably produced in
an unexpected reaction of the corresponding chloromethyl
quinazoline 3-oxide with methylamine.
H
N CH2Cl N NHCH3
..
CH3NH2 CH2Cl
N+ - N -
Cl O Cl + O

2. 6

CH3NH2
NHCH3. HCl
NHCH3 N
N CH2NHCH3 N

N+ - . .CH2 Cl Cl N+
O N O-
Cl Cl
OH

chlordiaz epoxide HCl

2. 3