Prepared by Mashruk Alam and Riaz Mahmud, A team of Researchsio.

1. Drug discovery, Design &
development basics

2. Introduction
Before the twentieth century, medicines consisted mainly of
herbs and potions, and it was not until the mid-nineteenth
century that the first serious efforts were made to isolate and
purify the active principles of those remedies. Since then,
many naturally occurring drugs have been obtained and their
structures have determined.
These natural products sparked off a major synthetic effort
where chemists made literally thousands of analogues in an
attempt to improve on what nature had provided.

3. Introduction
An overall pattern for drug discovery and drug development
evolved, but there was still a high element of trial and error
involved in the process.
In recent years, rapid advances in the biological sciences have
resulted in a much better understanding of how the body
functions at the cellular and the molecular level.
As a result, most research projects in the pharmaceutical
industry or university sector now begin by identifying a
suitable target in the body and designing a drug to interact with
that target.

4. Generally, we can identify the following stages in drug discovery,
design, and development:
Drug discovery: Finding a lead
• 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 if required

5. Drug design:
• Identify structure–activity relationships (SARs)
• Identify the pharmacophore
• Improve target interactions (pharmacodynamics)
• Improve pharmacokinetic properties
Drug development:
• Patent the drug
• Carry out preclinical trials (drug metabolism, toxicology,
formulation and stability tests, pharmacology studies, etc.)
• Design a manufacturing process
(chemical and process development)
• Carry out clinical trials
• Register and market

6. Drug discovery: Finding a lead

7. 1. Choosing a disease
The first step of drug discovery is of course choosing a disease.
Pharmaceutical companies have to consider economic factors, as
well as medical ones. A huge investment has to be made in the
research and development of a new drug. Therefore, companies
must ensure that they get a good financial return for their
investment.
2. Choosing a drug target
Once a therapeutic area has been identified, the next stage is to
identify a suitable drug target (e.g. receptor, enzyme, nucleic acid,
etc.).
Target specificity: Selectivity is important for drugs acting on
targets within the body. Enzyme inhibitors should only inhibit the
target enzyme and not some other enzyme.

8. 3. Identify Bioassay
Choosing the right bioassay or test system is crucial to the
success of a drug research program. The test should be simple,
quick, and relevant, as there are usually a large number of
compounds to be analyzed.
Human testing is not possible at such an early stage, so the test
has to be done in vitro (i.e. on isolated cells, tissues, enzymes,
or receptors) or in vivo (on animals).
Thus, in vitro tests are usually carried out first to determine
whether a drug interacts with its target, and in vivo tests are
then carried out to test pharmacokinetic properties.

9. Bioassay Techniques
High-throughput Screening (HTS):
Robotics and the miniaturization of in vitro tests on genetically modified cells has
led to a process called high-throughput screening (HTS), which is particularly
effective in identifying potential new lead compounds.
This involves the automated testing of large numbers of compounds versus a large
number of targets; typically, several thousand compounds can be tested at once in
30–50 biochemical tests.

10. Other techniques:
Screening by NMR
More recently, nuclear magnetic resonance (NMR)
spectroscopy has been used to detect whether a compound binds
to a protein target.
Affinity Screening
Surface Plasmon Resonance
Scintillation Proximity Assay
Isothermal Titration Calorimetry
Virtual Screening

11. 4. Finding a Lead Compound
Once a target and a testing system have been chosen, the next
stage is to find a lead compound—a compound which shows
the desired pharmacological activity.
The level of activity may not be very great and there may be
undesirable side effects, but the lead compound provides a start
for the drug design and development process.

12. There are various ways in which a lead compound might be discovered:
Screening of Natural Products
The Plant Kingdom
Microorganisms
Marine Sources
Animal Sources
Venoms and Toxins
Medical Folklore
Screening of Synthetic Compound “Libraries”
Existing Drugs
“Me Too” and “Me Better” Drugs
Enhancing a Side Effect
Starting from Natural Ligand or Modulator
Natural Ligands for Receptors
Natural Substrate for Enzymes
Enzyme Products as Lead Compounds
Natural Products as Lead Compounds
Combinatorial and Parallel Synthesis
Computer-aided Drug Design of Lead Compound

13. 5. Isolation and Purification
If the lead compound (or active principle ) is present in a
mixture of compounds from a natural source or a
combinatorial synthesis, it has to be isolated and purified.
The ease with which the active principle can be isolated and
purified depends very much on the structure, stability, and
quantity of the compound.

14. 6. Structure Determination
In the past, structures had to be degraded to simpler
compounds, which were further degraded to recognizable
fragments. From these scraps of evidence, a possible structure
was proposed, but the only sure way of proving the proposal
was to synthesize the structure and to compare.
Today, structure determination is a relatively straightforward
process. Methods used to determine structure includes X-ray
crystallography, NMR spectroscopy, mass spectroscopy, etc.

15. Drug Design

16. Drug Design - Introduction:
Once the lead compound has been discovered, it can be used
as the starting point for drug design.
There are various aims in drug design. The eventual drug
should have a good selectivity and level of activity for its
target, and have minimal side effects. It should be easily
synthesized and chemically stable. And finally, it should be
non-toxic and have acceptable pharmacokinetic properties.

17. Purpose of Drug Design
1.To improve the selectivity of the drug
The main purpose of the drug is to get the therapeutic effect
with lesser toxicity. In some cases, it has been observed that the
effective dose of the drug does not only show therapeutic
activity but also some toxicity. So sometimes it is important to
improve the selectivity of drug to reduce the toxicity or adverse
reaction.
For example, selective β1- blockers are safer for patients with
lung disease than nonselective β-blockers.

18. 2. To alter the ADME of the drug
Absorption:
Oral route of administration is always a convenient route.
But sometimes it is not possible for a drug to be given in
oral route because of poor absorption or lack of stability in
GIT.

19. Distribution:
Molecular modification can help to alter the distribution of the
drug.
For example, thiopental is developed from pentobarbital by
replacing one oxygen atom with sulfur.
Metabolism:
We can control the action of the drug by increasing or decreasing
the metabolism rate to shorten or prolong action of the drug
respectively.
For example, the development of procainamide from procaine.
Elimination:
Elimination can be a good factor to consider for molecular
modification. A drug should have an acceptable elimination rate.
If the drug is too polar, it is likely to be eliminated rapidly.

20. 3. To achieve more desired (drug-like) properties and less
toxicity
One of the main purposes of drug designing is to achieve more
desirable properties like potency, less toxicity, and specificity.
4. Modification to reduce cost
Modification of the lead compound is often done to make the
drug more affordable.
For example, the synthetic diethylstilbestrol offers more
affordability compared to the natural estrogenic hormones.

21. Identify structure–activity relationships (SARs):
Once the structure of a lead compound is known, the medicinal
chemist moves on to study its structure–activity relationships
(SAR). The aim is to identify those parts of the molecule that
are important to biological activity and those that are not.
In order to study the structure activity relationship of a lead
compound, we first have to identify which functional groups of
the lead that takes part in the binding interactions with the
target. In traditional approach, we develop analogs of the lead
compound by changing/modifying different functional groups
of the drug and test the activity of each of these analogs.

22. Identification of Pharmacophore:
Once it is established which groups are important for a
drug’s activity, it is possible to move on to the next stage—
the identification of the pharmacophore.
The pharmacophore summarizes the important binding
groups that are required for activity, and their relative
positions in space with respect to each other.

23. Drug optimization: Strategies in drug design
Once the important binding groups and pharmacophore of
the lead compound have been identified, it is possible to
synthesize analogues that contain the same
pharmacophore.
But why is this necessary? If the lead compound has useful
biological activity, why bother making analogues?
The answer is that very few lead compounds are ideal.
Most are likely to have low activity, poor selectivity, and
significant side effects.
They may also be difficult to synthesize, so there is an
advantage in finding analogues with improved properties.

24. This can be done by:
1. Variation of substituents ( alkyl, aromatic)
2. Extension of the structure
3. Chain extension/contraction
4. Ring expansion/contraction
5. Ring variation
6. Ring fusions
7. Isosteres and bioisosteres
8. Simplification of the structure
9. Rigidification of the structure
10. Conformation Blockers
11. Structure based drug design (Computer based drug design)
12. Drug design by NMR spectroscopy
13. Designing drugs to interact with more than one target

25. Optimizing hydrophilic/hydrophobic properties
The relative hydrophilic/hydrophobic properties of a drug are
crucial in influencing its solubility, absorption, distribution,
metabolism, and excretion (ADME).
Drugs which are too polar or too hydrophilic do not cross the
cell membranes of the gut wall easily. One way round this is to
inject them, but they cannot be used against intracellular targets
as they will not cross cell membranes. They are also likely to
have polar functional groups which will make them prone to
plasma protein binding, metabolic phase II conjugation
reactions, and rapid excretion.

26. Very hydrophobic drugs fare no better. If they are administered
orally, they are
likely to be dissolved in fat globules in the gut and will be poorly
absorbed. If they are injected, they are poorly soluble in blood and
are likely to be taken up by fat tissue, resulting in low circulating
levels.
It has also been observed that toxic metabolites are more likely to
be formed from hydrophobic drugs.

27. Strategies to optimize hydrophilic/hydrophobic properties
of the drug
1. Masking polar functional groups to decrease polarity
2. Adding or removing polar functional groups to vary polarity
3. Varying hydrophobic substituents to vary polarity
4. Variation of N-alkyl substituents to vary pKa
5. Variation of aromatic substituents to vary pKa
6. Bioisosteres for polar groups

28. Drug development:
• Patent the drug
• Carry out preclinical trials (drug metabolism, toxicology,
formulation and stability tests, pharmacology studies, etc.)
• Design a manufacturing process
(chemical and process development)
• Carry out clinical trials
• Register and market

29. Formulation Studies:
Involve developing a preparation of the drug which is both
stable and acceptable to the patient. ( Tablet, capsule, IV)
Pre-formulation involves characterization of a drugs physical,
chemical & mechanical properties in order to choose what
other ingredients should be used in the preparation.
Formulation studies then must consider such factors like
particle size, salt form, crystal polymorphism, pH and
solubility, as all of these can influence bioavailability.
Pharmacology Studies:
- Drugs mechanism of action
- Dose response relationship & drugs duration of action.

30. Clinical Trials:
Phase 1: Takes about a year, involves 200-300 healthy
volunteer. Drugs safety, pharmacokinetics and dose levels.
Phase 2: Last 2 years. Carried on patients to establish weather
the drug has the therapeutic property claimed and to study
pharmacokinetic property and short term safety and to define
best doses regimen.
Phase 3: Take about three years. Carried out same as phase 2
and different parts of the world with double blind process. (
comparing the activity of drug with placebo)
Phase4: The drug is marketed and prescribed, and still
monitored for any rare and unexpected side effects.

32. Reference:
1. Patrick GL, An Introduction to Medicinal Chemistry, 5th Ed.

33. Prepared By: Team Discipulus Magister
A Team Of Researchsio
Masruk Alam
Southeast University,
Pharmacy Dept.
Member,
Researchsio
Riaz Mahmood
Southeast University,
Pharmacy Dept.
Member & Ambasaador
Researchsio