Nanochemistry

NAN 601
Instructor:
Dr. Marinella Sandros

Lecture 23: Drug Design

1
 A Drug.

A substance used in the

diagnosis, treatment, or
prevention of a disease.

A drug is any chemical or

biological substance,
synthetic or non-synthetic

http://www.detox-center.com/images/3.jpg

2
 Discovery of Drugs
A drug is anything that affects the way an
organism works.

Drugs can be taken to enhance function,

such as a student drinking caffeine to
enhance alertness.

For now we only consider drugs which are

used to cure a disease.

3
 Man has found, by trial and error, which berries,
roots, leaves and barks could be used for
medicinal purposes to alleviate symptoms of
illness.

All ancient civilisations made discoveries in this

field

Chinese herbal remedies are probably the most

well known
 http://www.public-domain-image.com/plants/flowers/slides/iris-petals.jpg

Iris petals - for treating bruises

Liverwort - for treating liver ailments

http://en.wikipedia.org/wiki/File:Lunularia_cruciata.jpg
Goldenrod - for treating jaundice

en.wikipedia.org/wiki/Goldenrod
 Discovery of Drugs
A disease is often thought of as an
infection, where a bacteria, virus, or other
living thing invades the body.

However, a disease is anything which

affects the proper functioning of the body.

It can be an infection, a genetic disorder, or

the result of environmental conditions such
as malnourishment, poisoning, or stress.

6
 Discovery of Drugs
Engineers often find it easy to see the body as a
factory.

Individual organs can be seen as machinery. The

actual nuts, bolts, screwdrivers, and wrenches
that make up all the machinery are the
equivalent of proteins, little chunks of organic
material that move things around in the body
and attach them together.

Most of the work in our body is done by

proteins.

7
 Discovery of Drugs

The body contains thousands of different

kinds of proteins.

The construction of each is determined by the

DNA in the nucleus of each cell.

DNA may be thought of as long strings of

instructions which code for how each protein
is too be built.

8
 The DNA is just a long string of acids that
serves as a message about how to make
proteins.

Transcription, Translation and Protein Synthesis

http://www.labgrab.com/files/science-news/images/LabGrab/CentralDogma_0.jpg?1286382362
 The processes of new drug discovery and
development are long, complicated and
dependent upon the expertise of a wide
variety of scientific, technical and managerial
groups.

10
 Today there are at least 120 distinct chemical
substances derived from plants that are considered
important drug and are currently in use in one or
more countries in the world

Some of these drugs are simply a chemical or

chemicals extracted from plant materials and put
into a capsule, tablet or liquid.

Eg. In Germany a Cynarin drug is manufactured

and sold to treat hypertension, liver disorders and
highly cholesterol levels.

12
 The cynarin drug is simply an Artichoke liquid extract, that has
been concentrated and chemically manipulated to contain a specific
amount of this one chemical ; such a preparation is called a
standardized extract.

However in the U.S artichoke extracts are available as natural

products and sold in health food stores as dietary supplements

Some U.S artichoke products are even standardized to contain a

specific amount of cynarin, yet they can still be purchased here as a
natural product without a prescription.

There may be little to no difference between the Cynarin drug

produce in Germany and the artichoke standardized herbal
supplements made in the U.S considering that the same amount of
Cynarin is being delivered, dose for dose

13
 Consumers find it very frustrating to sort through a
lot of ambiguous information put out by natural
product manufacturers who cannot legally label
their goods with condition-specific.

http://www.nlm.nih.gov/medlineplus/images/pills5.jpg

14
 While many drugs have originated from medicinal
plants, medicine uses can be attributed to various
active chemicals found in them, there is a distinct
difference between using a medicinal plant and a
chemical drug.

The difference is one that scares most conventionally

trained doctors with no training in plants.

Drugs usually consist of a single chemical, whereas

medicinal plants can contain 400 or more chemicals.

Its relatively easy to figure out the activity and side

effects of a single chemical.

15
 Rev Edward Stone (1760s) searched along a
riverbank (i.e. a cold and wet place) for a plant-
based cure for the fevers associated with
influenza.

Found that the bark of the willow was effective in

reducing fever.

Native American Cherokees used willow bark for

such purposes for centuries.
* willow bark contains salicin

* metabolized in vivo to the active

agent salicylic acid

* salicylic acid and more tolerable

prodrug aspirin made in late 19th
century

* mechanism of action not

discovered until the1970s www.dermaxime.com/willow-bark.htm
 Analgesic (pain reliever)
Antipyritic (fever reducer)
Anti-inflammatory
Anticoagulent

History of Aspirin
- Hippocratus: powder made from the
bark and leaves of the willow tree to
help heal headaches, pains and fevers Inhibits production of
- Henri Leroux & Raffaele Piria:
purification of active ingradient from prostaglandins (pain
the plant
- 1899 Hoffman: formulation and patent messengers)
The synthesis involves the reaction of salicylic acid and acetic
anhydride in the presence of a catalyst, phosphoric acid, H3PO4.

wwwchem.csustan.edu/.../aspirincons.htm
Once the aspirin is prepared it must be isolated from the reaction solution and purified.
The aspirin is insoluble in cold water, and can be isolated by filtering the chilled
reaction solution.

Purification is necessary to remove any unreacted salicylic acid and acetic anhydride,
as well as the acetic acid product and phosphoric acid. Acetic anhydride is caused to
decompose by the addition of water once the formation of aspirin is complete:

(CH3CO)2O + H2O 2 CH3CO2H

Powdered dried bark of the
cinchona tree, a native of
South America, was made
into a drink and used by the
Quechua Indians of Peru to
treat fevers.
Discovered by Jesuit priests
in the 1620s, Barnab de
Cobo takes cinchona bark to http://www.mhhe.com/biosci/pae/botany/botany_map/articles

Europe in 1632 to treat

/images/bm_08-02.gif

malaria.
 Quinine isolated in 1820
by Pierre Joseph Pelletier
and JosephCaventou
First Total Synthesis
(1943) RB Woodward and
WE von Doering
Kills parasites causing http://en.wikipedia.org/wiki/File:Quinine.svg

malaria.
Mode of action complex
 The so-called 'father of
modern chemotherapy.

Original proponent of the

magic bullet he aimed to
use chemicals to treat
disease.

In 1910 the first fully

synthetic drug was made:
http://en.wikipedia.org/wiki/File:Paul_Ehrlich.png
Salvarsan which contained
arsenic!
 Used for treating sleeping sickness
(trypanosomiasis) and syphilis (caused by
Treponema pallidum).

http://en.wikipedia.org/wiki/File:Salvarsan-montage.png

The Nobel Prize for Medicine 1908

A bio(macro)molecule may be involved in a disease process, but
to be a drug target it has to be validated.

In other words shown to be critical in the disease process.

Useful techniques available are to validate a target are:

Gene knockout: does removal of the gene that encodes the

target protein result in, for example, the death of a pathogen
(disease causing microorganism)?

RNA interference (RNAi): involves double-stranded ribonucleic

acid (dsRNA) interfering with the expression of genes with
sequences complementary to the dsRNA. Results in a
reduction of the production of the protein (target) in
question.
 How specific does the interaction between a drug molecule and its
target have to be?
A rough and ready back of the envelope calculation shows:

Consider: an active compound MW 200 g mol-1

1 mole = 61023
Therefore 1 mg substance gives
(61023)(10-3/200) = 31018 molecules

A human has approximately 31013 cells giving

3 1018/31013 = 1105 molecules of active substance per cell
An erythrocyte (a typical cell) contains approx 1010 molecules
1 molecule of active substance per 100,000 cellular molecules
 The isolation of many bioactive products from
natural sources has led to the systematic screening
of plant and animal extracts for activity.
80% of the worlds population uses drugs
exclusively from natural sources.
35% of drugs contain principles (key structure
elements) of natural origin.
Less than 5% of the 500,000 higher plant species
have undergone biological pharmacological
screening.
Each plant has potentially 10,000 different
constituents.
 Research based pharmaceutical companies,
on average, spend about 20% of their sales on
research and development (R&D).
This percentage is significantly higher than in
most other industries, including electronics,
aerospace, automobiles, and computers.
Since 1980 US pharmaceutical companies
have practically doubled spending on R&D
every 5 yrs.
 Prodrugs are biologically inactive derivative of
an active drug intended to permeate certain
barriers in the parent drug such as toxicity,
instability, minimal solubility and non-
targeting capabilities.
The majority of drugs for cardiovascular
diseases undergo first-pass metabolism
resulting with drug inactivation and
generation of toxic metabolites, which makes
them appealing targets for prodrug design.
 Numerous therapeutic drugs for treating
cardiovascular ailments suffer from undesirable
properties after metabolism leading to drug
inactivation causing pharmacological,
pharmaceutical and pharmacokinetic barriers in
their clinical drug application.
To minimize these undesirable drug properties
while maintaining the drug therapeutic activity, the
prodrug approach was developed by covalently
linking the active drug to a chemical moiety thus
offering the utmost flexibility and at the same time
enhancing the drug efficacy.
 The universally accepted definition for a
prodrug is a pharmacologically inert chemical
drug that can be converted in vivo to the
active drug molecule enzymatically or non-
enzymatically while retaining its therapeutic
effect.
It is also worth noting that despite the fact
that prodrugs and anologs take on similar
structures, there are still some inherent
differences.
Mini Reviews in Medicinal Chemistry 2005, 5, 893-914.
 Therapeutic drugs for cardiovascular diseases
development soared because scientists were
able to investigate complex molecular
interactions that occur in the onset of disease
and overcome pharmacological barriers by
adapting to the prodrug approach.
In turn, the amalgamation of these two
developments provided a way to identify
genetic alterations and to screen for a wider
range of new drugs.
 Venous thromboembolism is a joint term for deep
vein thrombosis and pulmonary embolism, where a
blood clot is formed in a vein leading to major
organs.
Thrombin plays an intricate role in the
development of venous thromboembolism; for that
reason scientists were instigated to formulate
drugs that can block thrombin formation.
Platelets get promoted at the site of vascular injury
by thrombin and fibrinogens which are converted
to fibrins to offer stability for the surrounding
platelets
 Ximelagatran is quickly taken up in the
gastrointestinal tract and biologically
converted to melagatran.

Melagatran is known to inhibit the production

and the activity of human -thrombin with a
high binding affinity.
 There are several differences
between ximelagatran and
melagatran.
One ximelagatran contains an
ethyl group at the carboxylic end
and a hydroxyl group at the
amidine end.
Furthermore, at physiological pH
melagatran is highly charged
whereas ximelagatran is inert
and favor more lipopholic
environments.
Melagatran can be broken down
further in the body therefore it is
removed via the renal route.
 BIBR 1048 is also rapidly absorbed after oral
administration and converts to dabigatran
(BIBR 953) which is potent and selective for
inhibiting thrombin.
Circulation 2000, 101, (6), e76-80
 Monoclonal antibody c7E3 (abciximab),
epitifibatide and tirofiban.

Although these inhibitor drugs are effective in

lowering platelet aggregation, they can only
be administered intravenously and cannot be
given orally.
 An oral active prodrug was developed by
Boehringer Ingelheim, by the name of
lefradafiban which is converted to an inhibitor
drug fradafiban in the digestive system.

A clinical pharmacology phase I study

revealed that lefradafiban was able to inhibit
platelet aggregation.
 After percutaneous coronary intervention
(PCI), coronary stenting is performed to
reduce restenosis. Followed coronary
stenting, patients are given an antiplatelet
drug clopidogrel which has shown superior
efficacy in comparison to aspirin to inhibit
stent thrombosis.

Clopidogrel is inactive prodrug that is

oxidized in the liver by cytochrome P450 to
2-oxo-clopidogrel leading to an active acid
derivative metabolite
 The acid derivative of
clopidogrel releases its
antiplatelet effect by
generating a disulfide
bond with the platelet
P2Yac adenosine
diphosphate (ADP)
receptors.

Platelet aggregation is
interceded by P2Yac
(P2Y12) ADP receptor by
blocking adenyl cyclase.

Biochemical Pharmacology 1992, 44, (3), 527-532.

 17 -estradiol which is the most common
estrogen hormone found in humans, has
been linked to stop the initiation and the
development of atherosclerosis in animal
models.
 Once inside the body, 17 -estradiol is
metabolized to 2-methoxyestradiol (2-ME)
through methylation.

2-ME can block rat and human vascular

smooth muscle cells migration and
proliferation.
2-ME inhibits cell
division by blocking
the expression and
activation of cyclin
and cyclin-dependent
kinases (Cyclin-
D1/cdk4), the
expression of cdk
inhibitor p27, tubulin
polymerization and
the expression of
cyclooxygenase-2
 http://www.jove.com/video/2846/method-
for-novel-anti-cancer-drug-development-
using-tumor-explants-of-surgical-
specimens