Lecture 1 & 2: Drug Discovery and Development Pathway

Question 1

Drug Definition: FDA

Answer 1

An active ingredient that is intended to furnish pharmacological activity or other effect in the
diagnosis, cure, mitigation, treatment or prevention of a disease, or to affect the structure of any
function of the human body, but does not include intermediates used in the synthesis of such ingredients

Question 2

Drug Definition: Health Canada

Answer 2

An active ingredient is any component that has medicinal properties and supplies
pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention
of disease, or to affect the structure or any function of the body of man or other animals

Question 3

Drug Definition: Food and Drug Act

Answer 3

A drug includes any substance or mixture of substances manufactured, sold or
represented for use in:
(a) The diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical
state, or its symptoms, in human beings or a
(b) Animals
(c) Restoring corrective or modifying organic functions in human beings or animals
(d) Disinfection in premises in which food is manufactured, prepared or kept

Question 4

Drug Identification Number

Answer 4

computer-generated eight digit number assigned by Health
Canada to a drug product prior to being marketed in Canada. It uniquely identifies all drug products sold
in a dosage form in Canada and is located on the label of prescription and over-the-counter drug
products that have been evaluated and authorized for sale in Canada

Question 5

Characteristics of a DIN

Answer 5

● Manufacturer
● Product name
● Active ingredient(s)
● strength(s) of active ingredient(s)
● Pharmaceutical form
● Route of administration

Question 6

National Drug Code

Answer 6

unique 10-digit, 3-segment numeric identifier assigned to each drug
listed under section 510 of the US Federal, Food, Drug and Cosmetic Act
Labeler code (1): any firm that manufactures, repacks or distributes a drug product
Product code(2): identifies a specific strength, dosage form, and formulation for a particular firm
Package code(3): identifies package forms and sizes

Question 7

Chemical Name of Drug

Answer 7

Chemists can tell the structure of the molecule. Can have different chenical names if different conventions are used for naming

Question 8

Generic Name of Drug

Answer 8

Bears resemblance to the chemical name, most commonly used in scientific discussions,

Question 9

Trade name

Answer 9

Sold under patent

Question 10

Sources of Drug

Answer 10

Animal : insulin (pig, cow)
Plant: Digitalis (digitalis purpurea), morphine (papaver somniferum)
Inorganic : Calcium carbonate, lithium carbonate
Synthetic : most drugs, small molecules
Biotechnology : antibiotics (by fermentation), genetic manipulation/recombinant DNA (human insulin,
human growth factory, huma clotting factor)
2

Question 11

Chinese Medicine

Answer 11

Believed to have originated in the times of the legendary emperor Sheng Nong in 3500BC
● Chinese pharmacopoeia is extensive; some of the active ingredients from Chinese herbs have
been used in Western drugs
○ Rauwouofia - antihypertensive and emotional and
○ mental control
○ Alkaloid ephedrine from Mahuang - asthma
San Qi: Sheng Nong tried to kill a snake by beating it. Snake returned a few days later with no injuries and
the emperor kept beating it until he followed it and observed it. The snake crawled back into the bush
and ate a plant material known as San Qi - used for treating external injuries

Question 12

Egyptian Medicine

Answer 12

● Ancient papyrus provided written records of early Egyptian medical knowledge
● Ebers papyrus provided 877 prescriptions and recipes for internal medicine, eye and skin
problems and gynecology
● Kahun papyrus 1800BC: detailed treatments for gynecological problems
● Medications were based mainly on herbal products: myrrh, frankincense, castor oil, fennel, sienna,
thyme, linseed, aloe and garlic

Question 13

Indian Medicine

Answer 13

● The Indian folk medicine, Ayurvedic medicine, can be traced back 300-5000 years and was
practised by the Brahmin sages. The treatments were set out in sacred writings called Vedas
● Some herbs: cardamon, cinnamon
● Henbane: antivenom for snakebites

Question 14

Greek Medicine

Answer 14

● Derived from the Egyptians, Babylonians, Chinese and Indians
● Castor oil: laxative, linseed/flaxeed: soothing emollient, laxative, antitussive
● Fennel: relief of intestinal colic and gas, asafetida gum resin: antispasmodic
● Greatest Greek contribution: dispel notions that diseases are due to supernatural causes or spells
● Hippocrates (father of medicine): credited with laying down the ethics for physicians

Question 15

Before 20th Century

Answer 15

• natural sources
• prepared by individuals
• small scale
• not purified
• not standardized/tested
• limited administration
• no controls
• no idea of mechanism of action

Question 16

After 20th century

Answer 16

• Mainly synthetic sources
• prepared by companies
• massive scale
• highly purified
• standardized/tested
• world-wide administration
• tight legislative control
• mechanisms of action partly understood

Question 17

Drug Discovery

Answer 17

The process involved in finding a molecular candidate

Question 18

Drug Development

Answer 18

● Tests are performed on the lead compounds in test tubes (lab, in vitro) and on animals (in vivo) to
check how they affect the biological systems
● The tests, often called preclinical research activities include: toxicology, pharmacodynamics, and
pharmacokinetics as well as optimization of drug delivery systems
● An optimized compo und is found and this becomes a potential drug ready for clinical trials
in humans

Question 19

Rational Approach

Answer 19

Requires three-dimensional knowledge of the target structure involved in the disease. Drugs are designed to interact with this target structure to create a beneficial response
this is an emerging field in drug discovery started in the last 30 years

Question 20

Irrational Approach

Answer 20

• historical method of discovering and developing drugs
• involved empirical observation sof the pharmacological effects from the screening of many chemical compounds, mainly those from natural products
• the active component that gives rise to the observed effects is isolated
• the chemical formula is determined and modifications are made to improve its properties
  yielded many drugs available today

Question 21

Aspirin

Answer 21

(1) Hippocrates - white willow
(2) Johann Buchner - salicin
(3) Gerhardt - salicylic acid
(4) Hoffman - acetylsalicylic acid
(5) Bayer - aspirin powder
(6) - Bayer - liquid
(8) OTC - Aspirin becomes available without prescription
(9) Craven - heart attack
(10) Vane - inhibit generation of prostaglandins

Question 22

Penicillin

Answer 22

Discovered by Sir Alexander Fleming who
observed at St. Mary’s hospital in London that
mould had developed accidentally on a
staphylococcus culture plate - it created a
bacteria free circle around itself. Fleming A. On
the antibacterial action of cultures of
penicillium, with special reference to their use
in the isolation of B. influenzae
Using deep-tank fermentation, pharmaceutical company Pfizer was successful in its efforts to
mass-produce penicillin and becomes the world’s largest producer of the miracle drug
Infections that were previously severe and often fatal, like bacterial endocarditis, bacterial meningitis and
pneumococcal pneumonia, could be easily treated

Question 23

Insulin

Answer 23

A hormone which regulates sugar levels was discovered by Banting and Best under the supervision of
Macleod
They removed pancreas from dogs and the animals became diabetic. Then they extracted pancreas juices
and injected to a diabetic dog, and dog became free of disease symptoms

Question 24

Disease Selection

Answer 24

● Start from selection of disease and identification of target
● Management and marketing people play a significant role
● Disease selection based on the population affected
● Potential of new drug for financial return is critical
● Financial return provides resources for further research

Question 25

Choosing a drug target

Answer 25

● A key structure in our body (enzymes, ion channels, receptor protein, nucleic acid, gene) involved
in a particular disease related process. Ideally target should be disease specific
● In the past drugs were discovered before their molecular targets
● This information is obtained from basic research and knowledge of how systems work

Question 26

HIT identification

Answer 26

A molecule which will interfere with only the chosen target, but not
the other, related targets
Screening for Compound-Target Interaction
1) High-throughput screening (HTS)
● Find a molecule which will interfere with only the
chosen target, but not the other, related targets
● This method provides real results that are used for
drug discovery
● Requires synthesis
● Expensive
2) Virtual screening (VS) (in silico):
● Computational technique that simulate real screening
● Low costs
● No synthesis is necessary
● Huge amount of chemicals to search from
● The disadvantage of virtual screening is that it cannot substitute real screening

Question 27

Hit-to-Lead

Answer 27

2) Compounds with favourable affinity to targets are identified as hits (~1% of tested compounds)
3) Hits with best properties are selected as leads
1. Hit conformation
2. Selection of certain number of compounds-hits as leads
a. Drug-like properties
b. Affinity to target - magnetic effect
c. Chemical stability
d. Metabolic stability

Question 28

Lapinski’s Rule of 5

Answer 28

A rule of thumb to evaluate druglikedness or determine if a chemical compound with a certain
pharmacological or biological activity has properties that would make it likely to be orally active drug in
humans
The rule describes molecular properties important for a drug’s pharmacokinetics in the human body,
including their absorption, distribution, metabolism and excretion (ADME)

Question 29

To be orally active, a drug molecule should meet the following criteria

Answer 29

● No more than 5 hydrogen bond donors ( nitrogen or oxygen atoms with one or more hydrogen
atoms)
○ These bonds can influence polarity
● Not more than 10 hydrogen bond acceptors (nitrogen or oxygen atoms with free electron pair)
● A molecular weight under 500 daltons
○ Large - not going to get absorbed
○ Drug needs certain lipophilicity
● An octanol-water partition coefficient log P less than 5
○ Nice mix so it goes through the area well
Only one of the criteria can be violated. The rule does not predict if a compound is pharmacologically
active

Question 30

Lead optimization

Answer 30

The molecular properties of the lead are modified such that they interact in the best way with the target
Structural modification of biologically active compound (lead) in order to:
● Improve potency
● Reduce off-target activities, and
● Optimize physicochemical/metabolic properties suggestive of reasonable in vivo pharmacokinetics
(ADME)
● Accomplished through chemical modification of the structure

Question 31

Pharmacore and Lead Optimization

Answer 31

● Pharmacore: a set of structural features in a molecule that is recognized at a receptor site and is
essential for that molecule’s biological activity
● Structural features: functional groups, their positions and spatial orientation
● Pharmacore must be preserved during lead optimization, otherwise the activity is lost

Question 32

First Beta-blocker propranolol

Answer 32

Scottish scientist James W. Black successfully developed propranolol in the late 1950s. He was awarded
the Nobel Prize in Medicine for this discovery in 1988

Question 33

Example: Smoking cessation drugs - varenicline vs bupropion

Answer 33

● Bupropion (Wellbutrin) - an antidepressant that was discovered by serendipity. Substituted
amphetamine, primary action is dopamine/norepinephrine reuptake inhibition
○ No one was really looking to figure out that wellbutrin works for smoking cessation
○ Gave this drug to people with depression, they ended up not smoking as much
○ It helped people quit smoking better than current treatment at the time
● Nicotine replacement therapy is another approach
Why is varenicline better?
● Most treatments for drug dependence only target the negative effects of withdrawal. Varenicline is
one of the only treatments for any substance dependence that also works on the positive effects
of the drug
○ Looking to target those negative effects of
withdrawal
○ Looks at positive effects of the drugs
○ Look at the effect of a partial agonist
○ Binds with receptor with high affinity
○ It will block the effect
○ Partial agonism of the receptor

Question 34

Major areas in the pharmaceutical industry

Answer 34

> antidiabetic > analgesic > rare disease >

anti-inflammatory > recombinant vaccine > cognition enhancer