Drug discovery, design and

development

• Dr. Husnul Khotimah, Ssi, Mkes

• Lab. Farmakologi FKUB
• Husnul_zq@yahoo.com
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 these
remedies (i.e. the pure chemicals responsible for the
medicinal properties). The success of these efforts led to
the birth of many of the pharmaceutical companies we
know today.
• Since then, many naturally occurring drugs have been
obtained and their structures determined (e.g. morphine
from opium, cocaine from coca leaves, quinine from the
bark of the cinchona tree).
• An overall pattern for drug discovery and drug
development also evolved, but there was still a high
element of trial and error involved in the process.The
mechanism by which a drug worked at the molecular level
was rarely understood, and drug research focused very
much on what is known as the lead compound: an active
principle isolated from a natural source or a synthetic
compound prepared in the laboratory.
Drug discovery, design and development: the
present
• In recent years, medicinal chemistry has undergone a
revolutionary change
• 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.
An understanding of the structure and function of the target, as well as the
mechanism by which it interacts with potential drugs is crucial to this
approach.

• Drug discovery: finding a lead

• Drug design
• Drug development

• Many of these stages run concurrently and are dependent

on each other.
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
necessary.
• Find a “lead compound”
“lead compound” = structure that has some activity against
the chosen target, but not yet good enough to be the drug
itself.
• If not known, determine the structure of the “lead compound”
Drug design
• Identify structure-activity relationships (SARs).
• Identify the pharmacophore.
• Improve target interactions (pharmacodynamics).
• Improve pharmacokinetic properties.
• Synthesize analogs of the lead
• Identify Structure-Activity-Relationships (SAR’s)
• Synthesize analogs of the lead
• Identify Structure-Activity-Relationships (SAR’s)
• Identify the “pharmacophore”
pharmacophore = the structural features directly
responsible for activity
• Optimize structure to improve interactions with
target
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 the drug.
• Make money!
• Determine toxicity and efficacy in animal models.
• Determine pharmacodynamics and pharmacokinetics of the
drug.
• Pharmacodynamics explores what a drug does to the body,
whereas pharmacokinetics explores what the body does to the
drug.
• Patent the drug
• Continue to study drug metabolism
• Continue to test for toxicity
• Design a manufacturing process
• Carry out clinical trials
• Market the drug
Current Procces of Drug Discovery
 Selectivity is Important!

• e.g. targeting a bacterial enzyme, which is not present

in mammals, or which has significant structural
differences from the corresponding enzyme in
mammals
The Standards are Being Raised

• More is known about the biological chemistry of living

systems
• For example: Targeting one subtype of receptor may enable
the pharmaceutical chemist to avoid potentially troublesome
side effects
Problems can arise

• Example: The chosen target, may over time, lose

its sensitivity to the drug
• Example: The penicillin-binding-protein (PBP)
known to the the primary target of penicillin in the
bacterial species Staphylococcus aureus has
evolved a mutant form that no longer recognizes
penicillin.
 Choosing the Bioassay
• Definitions:
• In vitro: In an artificial environment, as in a test
tube or culture media
• In vivo: In the living body, referring to tests
conducted in living animals
• Ex vivo: Usually refers to doing the test on a
tissue taken from a living organism.
Choosing the Bioassay (cont.)

In vitro testing
• Has advantages in terms of speed and requires relatively
small amounts of compound
• Speed may be increased to the point where it is possible
to analyze several hundred compounds in a single day
(high throughput screening)
• Results may not translate to living animals
 Choosing the Bioassay (cont.)

In vivo tests
• More expensive
• May cause suffering to animals
• Results may be clouded by interference with other biological
systems
Finding the Lead

Screening Natural Products

• Plants, microbes, the marine world, and animals, all
provide a rich source of structurally complex natural
products.
• It is necessary to have a quick assay for the desired
biological activity and to be able to separate the
bioactive compound from the other inactive substances
• Lastly, a structural determination will need to be
made
Finding the Lead (cont.)

Screening synthetic banks

• Pharmaceutical companies have prepared thousands
of compounds
• These are stored (in the freezer!), cataloged and
screened on new targets as these new targets are
identified
Finding the Lead (cont.)

Using Someone Else’s Lead

• Design structure which is similar to existing lead, but
different enough to avoid patent restrictions.
• Sometimes this can lead to dramatic improvements in
biological activity and pharmacokinetic profile. (e.g.
modern penicillins are much better drugs than original
discovery).
Finding the Lead (cont.)
Enhance a side effect
Use structural similarity to a natural ligand
 Computer-Assisted Drug Design
• If one knows the precise molecular structure of the
target (enzyme or receptor), then one can use a
computer to design a perfectly-fitting ligand.
• Drawbacks: Most commercially available programs
do not allow conformational movement in the target
(as the ligand is being designed and/or docked into
the active site). Thus, most programs are somewhat
inaccurate representations of reality.
 Structure-Activity-Relationships (SAR’s)

• Once a lead has been discovered, it is important to

understand precisely which structural features are
responsible for its biological activity (i.e. to identify
the “pharmacophore”)
The pharmacophore is the precise section of the molecule that
is responsible for biological activity
 Clinical Trials
• Phase I: Drug is tested on healthy volunteers
to determine toxicity relative to dose and to
screen for unexpected side effects
Phase I

•small group of people (20-80)

•individuals do NOT have disease
•evaluate its safety; common side effects:
•Fatigue, nausea, hair loss, vomiting
•determine a safe dosage range
•identify side effects
•0.5-1.5 years
Pharmacokinetics
• How drug is:
• Absorbed
• Metabolized
• Excreted
• Duration of action
Clinical Trials
• Phase II: Drug is tested on small group of patients to
see if drug has any beneficial effect and to determine
the dose level needed for this effect.
Phase II

•larger group of people (100-300)

• people with disease
•effectiveness
•further evaluate its safety
•dosage
•2 years
Clinical Trials
• Phase III: Drug is tested on much larger group
of patients and compared with existing
treatments and with a placebo
Phase III
•large groups of people (1,000-3,000)

•to confirm its effectiveness

•monitor side effects

•compare it to commonly used treatments

•Interactions (with other meds)

•Multicenter trial – many docs; many hospitals

Phase III
• May be vs. placebo:
• Placebo effect: measurable, desirable effect;
patients don’t know if on drug or placebo
• Patient feels better even if on placebo
• Often seen with antidepressants, antianxiety
meds
Clinical Trials
• Phase IV: Drug is placed on the market and patients
are monitored for side effects
Launch Drug
Phase IV

•after the drug or treatment has been marketed

•collect information about their effect in various populations

•side effects associated with long-term use.

•New indications: impt for company to extend its patent

protection.
•Eg. Prozac – antianxiety, approved recently for PMDD
(premenstrual dysorphic disorder)
Issues
Pharmacokinetics
how quickly drug is absorbed
eliminated from body (clearance)

Delivery Problem – injection vs. oral delivery

Do patients develop tolerance?

Pharmacogenetics

Interfere with meds for other diseases – eg. Lower bp

but interfere with med for type II diabetes
Placebo

• When don’t you use a placebo?

• Drug available already to treat disease

• Unethical to use placebo
 Discovery:
Good Laboratory Practices (GLP)

Development:
Good Manufacturing Practices (GMP)

Standard Operating Practices (SOP)

Documentation, Documentation, Documentation

 Modern drug discovery process

Target Target Lead Lead Preclinical Drug

identification validation identification optimization phase discovery

6-9 years
2-5 years

• Drug discovery is an expensive process involving high R & D cost and

extensive clinical testing
• A typical development time is estimated to be 10-15 years.
Bioinformatics tools in DD

• Comparison of Sequences: Identify targets

• Homology modelling: active site prediction
• Systems Biology: Identify targets
• Databases: Manage information
• In silico screening (Ligand based, receptor based):
Iterative steps of Molecular docking.
• Pharmacogenomic databases: assist safety related issues
 Currently used drug targets

J. Drews Science 287, 1960 -1964 (2000)

This information is used by bioinformaticians to narrow the search in the group

Insilico methods in Drug Discovery
• Molecular docking
• Virtual High through put screening.
• QSAR (Quantitative structure-activity relationship)
• Pharmacophore mapping
• Fragment based screening
 Molecular Docking

• Docking is the computational determination of binding

affinity between molecules (protein structure and ligand).
• Given a protein and a ligand find out the binding free
energy of the complex formed by docking them.

L
L R
R
Molecular Docking: classification
• Docking or Computer aided drug designing can be broadly
classified
• Receptor based methods- make use of the structure of the target
protein.
• Ligand based methods- based on the known inhibitors
Molecular Docking (SuperPred)
Does Asiatic acid have driving force
to TrkB ? : HEX 6.12
• Asiatic acid is not stimulate BDNF to its receptor (TrkB)
 change complex interaction
Docking (Autodock Vina on PyRx 0.8), Molecular interaction
(Ligand Scout V.2.0), Molecular visualization (chimera 1.8.1)

Energy binding afinity

Asiatic acid to PTP-1B :
-6.2 Kcal/mol
Inhibitor PTP-1B (BMP) interact with PTP-1B

Asiatic acid and BMP binds to the same site to PTP-1B : TYR46,
VAL49, PHE182, ILE 219 by hydrophobic interaction
Summary: role of Bioinformatics?
• Identification of homologs of functional proteins (motif,
protein families, domains)
• Identification of targets by cross species examination
• Visualization of molecular models
• Docking, vHTS
• QSAR, Pharmacophore mapping
 National Nanotechnology Initiative (NNI):

• Nanotechnology is the understanding and control of matter at dimensions of

roughly 1 to 100 nanometers. At the nanoscale, the physical, chemical, and
biological properties of materials differ in fundamental and valuable ways from the
properties of individual atoms and molecules or bulk matter.

NCI Cancer Nanotechnology Plan (July 2004):

• Nanotechnology refers to the interactions of cellular and molecular components

and engineered materials - typically clusters of atoms, molecules, and molecular
fragments - at the most elemental level of biology. Such nanoscale objects -
typically, though not exclusively, with dimensions smaller than 100 nanometers -
can be useful by themselves or as part of larger devices containing multiple
nanoscale objects.
 What is nanomedicine?

• Nanomedicine is defined as medical application of nanotechnology.

• include a wide range of applications, including biosensors, tissue engineering,

diagnostic devices, and many others

• Must provide special characteristics – e.g., novel

physical characteristics, unique delivery, cellular
penetration, receptor binding, targeting
• to more effectively diagnose, treat, and prevent various diseases.

• Today, nanomedicines has been accepted globally to

improve the treatments and lives of patients suffering from
a range of disorders
• including ovarian and breast cancer, kidney disease, fungal infections,
elevated cholesterol, menopausal symptoms, multiple sclerosis, chronic pain,
asthma and emphysema.
12/5/2017
 This illustrative figure shows the different structures of nanomedicines and their
approximate sizes. For comparison the sizes of biological nanostructures are shown at
the top of the figure. 
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Types of nanodelivery systems
 • …with natural products
ingredients
• Stability of • Poor solubility in
• Low bioavailability
bioactives water

Nanoparticles

Controlled
Improve stability Improve targeting
released kinetics

Enhanced uptake functionality

• Advantages of delivery system
• Increase in surface area
• Improved solubility of hydrophilic drugs
• Protect / encapsulate drugs from degradation
• Reduced immunogenic potential

• Disadvantages of delivery system

• Toxicity issue
• Small size
• Favourable shape
• physical interaction with cellular membrane and organelles
• Induces immunological reactions
• Short / long term accumulation
• Degradation of products
THANK YOU