Drug Discovery and

Development
Brief Overview
 Introduction

● New drugs are continually required by the healthcare systems to address unmet
medical needs across diverse therapeutic areas.
● Therefore pharmaceutical industries strive to deliver new drugs to the market
through the complex activities of drug discovery and development.

Discovery involves a number of processes like:

● target identification and validation,
● hit identification,
● lead generation and optimization and
● finally the identification of a candidate for further development.
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Introduction

Development, on the other hand, includes

● optimization of chemical synthesis and its formulation,
● toxicological studies in animals,
● clinical trials, and eventually
● regulatory approval.
● Both of these processes are time-consuming and expensive.
● Currently the industry is under pressure owing to the extremely stringent
regulatory requirements, environmental concerns, and reduced incomes due
to patent expirations.
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Stages of Drug discovery & Development

➔ Target identification ➔ Formulation and development

➔ Target validation
➔ lead identification
➔ lead optimization
➔ Product characterization
➔ Preclinical research
➔ Investigational New Drug (IND)
➔ Clinical trials
➔ New Drug Application (NDA)
➔ Approval

The average time required to bring a new

drug into the market ranges from 12-15 years
at an average cost of $600 to 800 million.

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Stages of Drug discovery & Development

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 Drug discovery and development
The discovery phase The development phase
Pre-discovery Pre-clinical testing
Gather as much information as possible about the In vitro and in vivo testing to determine if the drug is safe
disease and try to understand its nature. enough for human testing.
Target identification Clinical trial exceptions (CTX) applications
Choose a molecule in the body to target with a drug; File CTX with appropriate authorities before clinical testing
often a protein. can begin.
Target validation Phase 1 clinical trial
Test the target and confirm its role in the disease. Initial human testing in a small group of healthy volunteers.
Drug discovery Phase 2 clinical trial
Find a promising molecule (a ‘lead compound’) that Test in a small group of patients.
could become a drug. Phase 3 clinical trial
Early safety tests Test in a large group of patients to show safety and efficacy.
Initial tests on lead compounds, including Marketing authorisation application
pharmacokinetics, by experiment and/or computer Apply to appropriate authorities for approval.
modelling. Manufacturing
Lead optimisation Begin full-scale production.
Alter the structure of lead candidates to improve On-going studies and Phase 4 trials
properties; this may include formulation, delivery Continuing monitoring and checking of the drug in use.
mechanism and scale-up.

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 What is a Target?

● A target is a molecule that the drug needs to find and act upon. Often it is a protein molecule such
as an enzyme.

● The starting point for the design of new drug is an understanding at the molecular level of the
disease to be treated.

● Target for drug design usually fall into three categories: enzymes, receptors and nucleic acids.

● There are potentially many ways in which biochemical pathways could become abnormal and result
in disease. Therefore knowledge of the disease is important in order to select a target which disrupt
the process.

● Modern technologies allow chemists to work out the molecular structure of a target molecule and
represent it using physical or computer-generated models. This enables them to investigate the
interaction of potential drug molecules with the target.
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 What is a ‘Lead’ compound?

● With the target identified, thousands of compounds are made using a

technique called combinatorial chemistry.

● These are narrowed down to one compound to be studied further. This is

the lead compound.

● Lead Compound: A lead drug is the first member of a new class of

compounds possessing a good level of drug action for a specific disease.

● The lead compound is then chemically modified to produce a very large

number of structurally similar compounds, sometimes even upto
20,000.

● From these, the most likely one is chosen for pre-clinical testing. This is
followed by scaling up, through pilot scale to manufacture.
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 Lead compound

Examples:

1. Prontosil from which sulphanilamide, 2. Quinine, an antimalarial drug.

sulphadiazine and sulphamethoxazole have
been discovered.

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 Drug design based on target structure

● Structure based Drug Design (or direct drug design) relies on

knowledge of the three dimensional structure of the biological target
obtained through methods such as X-ray crystallography or NMR
spectroscopy.

● If an experimental structure of a target is not available , it may be

possible to create a homology model of the target based on the
experimental structure of a related protein.

● Using the structure of the biological target , candidate drugs that are
predicted to bind with high affinity and selectivity to the target may be
designed using interactive graphics and the intuition of a medicinal
chemist.

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 Drug design based on target structure

● Once the structure and target site is identified, there are several paths to
develop a good lead based on the structure of the target. These paths are
classified as computer aided versus experimental.

● An example of an experimental method is high-throughput

screening with combinatorial chemistry, in which thousands of
compounds are tested for biochemical effects.

● The computer-aided methods can be further classified into three

categories: inspection, virtual screening, and de novo
generation.

● In the first category, inspection, known molecules that bind the site are
modified to become inhibitors based on maximizing complementary
interactions in the target site.
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 Drug design based on target structure

● In virtual screening, databases of available small molecules are docked into the region of interest in
silico and scored based on predicted interactions with the site.
● Finally, for de novo generation (de novo drug design) small fragments of molecules, such as
benzene rings, carbonyl groups, amino groups, etc., are positioned in the site, scored, and linked in silico.
The final compounds, created in silico from the linked fragments, then must be synthesized in the
laboratory.

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De novo drug design

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Lead based drug design

● Once a target and testing system have been chosen, the next stage is to find a lead
compound.
● A lead compound is a compound which shows the desired therapeutic activity.
● The level of the activity may not be very great and there may be undesirable side
effects.
● The lead compound provides a start for the drug design and development process.
●

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Lead based drug design

There are various ways in which a lead compound might be discovered. They include:

1. Screening of natural products (the plant kingdom, the microbial world, the marine world,
animal sources, venoms and toxins)
2. Medical folklore
3. Screening synthetic compound libraries
4. Existing drugs / Me too drugs
5. Starting from natural ligand
6. Combinatorial synthesis
7. Computer aided drug design
8. Serendipity
9. Designing lead compounds by NMR

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 Lead based drug design

● If a lead compound is present in a mixture, then it has

to be isolated and purified.
● Later the structure of the lead compound can be
determined by techniques like X-ray crystallography
and NMR spectroscopy.
Drug design includes

● Optimizing target interactions:

● 1. Identify SARs
● 2. Identify the pharmacophore
● 3. Drug optimization - by variation in substituents,
extension of the structure, simplification of the
structure, rigidification of the structure etc.

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Lead based drug design

Optimizing access to the target:

1. Improving absorption - by variation of alkyl/acyl substituents, varying polar

functional groups to vary polarity and variation of N-alkyl substituents/aromatic
substituents to vary pKa.
2. Making drugs more/less resistant to chemical/enzymatic degradation
3. Targeting drugs - Ex. which target tumour cells/gastrointestinal tract.
4. Reducing toxicity
5. Prodrugs - to improve membrane permeability / prolong drug activity / to mask drug
toxicity & side effects / to lower water solubility.

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 Lead based drug design

The above mentioned experiments give information on:

● How the drug is absorbed, distributed, metabolized, and excreted.

● Its potential benefits and mechanisms of action.
● The best dosage.
● The best way to give the drug (such as by mouth or injection).
● Side effects or adverse events that can often be referred to as toxicity.
● How it affects different groups of people (such as by gender, race, or
ethnicity) differently.
● How it interacts with other drugs and treatments.
● Its effectiveness as compared with similar drugs.

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 Lead based drug design - An example

● Histamine triggers release of stomach acid. To stop acidity, histamine antagonist is required.
● Now histamine is the biological target.
● So, histamine analogs were synthesized with systematically varied structures and screened.
● N-guanyl-histamine showed some antagonist properties = LEAD compound.

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 Lead based drug design - An example

A. Chemical modifications were made of the

lead = LEAD OPTIMIZATION
B. More potent and orally active, but
thiourea found to be toxic in clinical A B
trials
C. Replacement of the group led to an
D
effective and well-tolerated product
D. Eventually replaced by Zantac with an
C
improved safety profile

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 Computer Aided Drug Design (CADD) / Molecular Docking

● Computers are essential tool in modern medicinal chemistry and are

important in both drug discovery and development.
● The development of this powerful tool enabled the chemist to predict the
structure and the value of the properties of known, unknown, stable and
unstable molecular species using mathematical equations. Solving the
equations gives required data.
● Graphical package converts the data for the structure of a chemical
species into a variety of visual formats. Consequently, in Medicinal
Chemistry, it is now possible to visualize the three dimensional shape of
both the ligands and their target sites.

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Computer Aided Drug Design (CADD) / Molecular Docking
● CADD uses computational chemistry to discover,
enhance or study drugs and related biologically
active molecules.
● The most fundamental goal is to predict whether a
given molecule will bind to a target and if so how
strongly.
● CADD is more often used to predict the conformation
of the small molecule and to model conformational
changes in the biological target that may occur
when the small molecule binds to it.

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 Computer Aided Drug Design (CADD) / Molecular Docking

Drug design with the help of computers may be used at any of the following stages of drug discovery:

1. Hit identification using virtual screening (structure - based drug design)

2. Hit-to-lead optimization of affinity and selectivity (structure-based design, QSAR)
3. Lead optimization: optimization of other pharmaceutical properties while maintaining affinity.

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 Computer Aided Drug Design (CADD) / Molecular Docking

Objectives of CADD:

1. To dock small molecules into macromolecules

2. To map pharmacophore group or ligands
3. To analyze relationship between chemical structure and
biological activity
4. To predict activity of compounds/analogues before the
synthesis

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 Computer Aided Drug Design (CADD) / Molecular Docking

Methods:

1. Virtual screening: The first method is identification of new ligands for a given receptor by searching
large databases of 3D structures of small molecules to find those fitting the binding pocket of the
receptor using fast approximate docking programs.
2. de novo design of new ligands: In this method, ligand molecules are built up within the constraint
of the binding pocket by assembling small pieces in a stepwise manner. These pieces can be either
individual atoms or molecular fragments. The key advantage of is that novel structures can be
suggested.
3. Optimization of known ligands by evaluating proposed analogs within the binding cavity.

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 Computer Aided Drug Design (CADD) / Molecular Docking

Docking & Scoring:

● Docking attempts to find the “best” matching between

two molecules.
● It helps in finding the ‘Right Key for the Lock’.
● To place a ligand (small molecule) into the binding site
of a receptor in the manner appropriate for optimal
interactions with a receptor.
● To evaluate the ligand-receptor interactions in a way
that may discriminate the experimentally observed
model from others and estimate the binding affinity.

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Computer Aided Drug Design (CADD) / Molecular Docking

Advantages of CADD:

● Time
● Cost
● Accuracy
● Information about the disease
● Screening is reduced
● Less manpower required

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 Computer Aided Drug Design (CADD) / Molecular Docking

Applications of CADD:

1. Use of computing power to streamline drug discovery and development process.

2. Leverage of chemical and biological information about ligands and targets to identify and optimize new
drugs.
3. Design of in silico filters to eliminate compounds with undesirable properties and select the most
promising candidates.

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Clinical trials

● Clinical trial is a systematic investigation in human subjects for evaluating

the safety & efficacy of any new drug.
● Clinical trials are a set of tests in medical research and drug development
that generate safety and efficacy data for health interventions in human
beings.

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Clinical trials

Drug action depends on:

● pharmacodynamics
● pharmacokinetics and dose regimen
● drug interactions
● receptor sensitivity of patient
● mood/personality of patient & doctor
● patients expectations and past experience
● social environment of patient
● clinical state of patient
Clinical trial controls these variables and examines action of
drug in defined set of circumstances

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 Clinical trials

● {Phase 0 (non-clinical)}
● Phase 1 (volunteers)
● Phase 2 (patients)
● Phase 3 (large scale multi-centre)
● Phase 4 (post registration monitoring)
● phases can also be defined by the
information you are trying to get out of
the testing

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Volunteer studies (phase I trials)

● pharmacologists & employees (15-30 in number)

● ethical approval
● healthy
● informed consent
● full resuscitation + medical backup
● monitor
● single and repeat doses
● increase dose levels

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Volunteer studies (phase I trials)

Objectives:

● metabolic and excretory pathways (impinges on toxicity

testing in animals)
● variability between individuals; effect of route;
bioavailability
● tolerated dose range
● indication of therapeutic effects
● indication of side effects

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 Volunteer studies (phase II trials)

● 150-350 ill people; informed consent

● needs license
● maximum monitoring; full resuscitation
● often patients where other treatment failed
Objectives:
● indication for use; type of patient; severity of
disease;
● dose range, schedule and increment;
● pharmacokinetic studies in ill people;
● nature of side effects and severity;
● effects in special groups.

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Volunteer studies (phase III trials)

● 1500-3500 ill patients

● multicentre?
● more certain data for the objectives of phase 2 studies
● interactions between drugs start to become measurable
in the larger population
● sub-groups start to be established
● special features and problems show up

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 Approval : New Drug Application (NDA)

● Formal proposal for the FDA to approve a new drug

for the sale
● Sufficient evidence is provided to FDA to establish:
● Drug is safe and effective
● Benefits outweigh the risks
● Proposed labelling is appropriate
● NDA contains all the information gathered during
preclinical to phase III.
● NDA can be thousands of pages long.
● Can take 2-3 years for FDA to review.

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Phase IV trials

● Done after the drug is being marketed.

● Confirm the efficacy and safety profile in large
populations during practice.
● Detect the unknown / rare adverse drug reaction/s
● Evaluation of over-dosage.
● Identification of new indications.
● Dose refinement: Evaluation of new formulations,
dosages, duration of treatment.

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DOSEWISE CLASSIFICATION OF DRUGS

● Each patient differs in their response to drugs

● Doses are prepared to give therapeutic effect to the patient based on the
average requirement

● FACTORS WHICH INFLUENCE EFFECT OF DRUGS

● BODY WEIGHT – average dose – mg/kg

● AGE – pharmacokinetics of drugs vary with age
● Metabolic power of liver & gastric pH changes with age
● DIET – Medicines are given after food to reduce gastric irritation. Food intake
decreases rate of drug absorption Some drugs are given on empty stomach
• GENETIC FACTORS – science of pharmacokinetics depend on genetic variation to
drug response
•ROUTE OF ADMINISTRATION – Intravenous doses are smaller than oral doses & is
faster in action
• EMOTIONAL FACTORS – Physicians personality influences the drug effect
considerably especially for psychosomatic disorders – sometimes placebos produce
therapeutic effect
• METABOLIC DISTURBANCE – changes in water , electrolytic balance, acid-base
balance, body temp etc modify drug effect
• PRESENCE OF DISEASE – Drugs like Barbiturates produce prolonged effects,
•Antibiotics are excreted by kidneys – if kidney function is impaired they become
toxic
•Pulmonary & gastrointestinal diseases may alter pharmacokinetics of drugs
FORMULATION OF CIPROFLOXACIN AN ANTIBACTERIAL DRUG

Film-coated tablets are available in 100-mg, 250-mg, 500-mg and 750-mg

✔ Ciprofloxacin Hydrochloride = drug
✔ Microcrystalline cellulose = binder , diluent , disintegrant , lubricant
✔ Cornstarch = binder ,disintegrant
✔ Lactose = diluent
✔ Polyvinyl pyrrolidene & sodium starch glycolate syrup = stabilizing & suspending agent
✔ magnesium stearate = lubricant
✔ hydroxypropyl methylcellulose = binder
✔ titanium dioxide = colorant
✔ and water.
✔ silicon dioxide, crospovidone polyethylene glycol
❖ Ciprofloxacin Oral Suspension is available in 5% (5 g ciprofloxacin in 100 mL) and
10% (10 g ciprofloxacin in 100 mL) strengths.
❖ Ciprofloxacin Oral Suspension is a white to slightly yellowish suspension with
strawberry flavor which may contain
yellow-orange droplets.
❖ It is composed of ciprofloxacin microcapsules and
diluent which are mixed prior to dispensing
❖ The components of the suspension have the
following compositions:

❖ Microcapsules - ciprofloxacin, polyvinylpyrrolidone, methacrylic acid copolymer,

hydroxypropyl methylcellulose, magnesium stearate, and Polysorbate
❖ Diluent - medium-chain triglycerides, sucrose, lecithin, water, and strawberry flavor