Lecture 2

Question 1

What is drug discovery?

Answer 1

a process during which a synthetic or naturally-occurring chemical (drug lead) is found to have a profile of biological activities that can be applied for disease treatment.

Question 2

Name some environmental influences that lead to diseases.

Answer 2

1. long-term phenotype changes sucg as weight gain, muscle weakness or depression
2. stressful environment
3. smoking (initiated as a result of social factors)

Question 3

What does exposure to stressful environment lead to?

Answer 3

activate hypothalamopituitary system and therby increase adrenal steroid secretion, which affects:

1. gene transcription in cells and tissues
2. salt metabolism
3. immune responses

Question 4

The increase in adrenal steroid secretion affects:

Answer 4

1. gene transcription in cells and tissues
2. salt metabolism
3. immune responses

Question 5

What are some of the issues with current drug discovery process?

Answer 5

1. long time between initial conception and final marketing
2. high attrition rate: 1 out of 5000 compound
3. costly process

Question 6

What are some potential ways to improve drug discovery process?

Answer 6

1. identify and validate more targets in a faster pace
2. eliminate problematic candidates earlier to reduce costs
3. enable targeted therapeutics

Question 7

What is the choice of therapeutic area often based on?

Answer 7

1. Available expertise and technology
2. Patent positions
3. Pharmaeconomics
4. Unmet medical need
5. Potential market size and patient population
6. Existing competition and market dominance

Question 8

Define orphan drug

Answer 8

a pharmaceutical agent that has been developed specifically to treat a rare medical condition (an orphan disease) that inflicts less than 200,000.

Question 9

The assignment of orphan status has resulted in medical breakthroughs that
would not have otherwise been achieved due to the economics of drug
research and development.

True or false

Answer 9

True

Question 10

How do orphan drug regulations assist in the development of orphan drugs as it may have poor pharmaeconomics?

Answer 10

• fewer patients can be tested for phase III clinical trials as it is an orphan disease

Question 11

What interventions are provided by the gpvernment on behalf of orphan drug development?

Answer 11

1. tax inxentives
2. enhanced patent protection and marketing rights
3. clinical research financial subsidization
4. creating gov’t run enterprise to engage in research and development

Question 12

Name an orphan disease

Answer 12

Blepharospasm

-Overactive blinking, eventually leading to the inability to open the eye lids and thus
blindness
-treated with Botox (botulinium toxin type A)

Question 13

List some age-related diseases

Answer 13

Alzheimer’s disease
Cancer
Chronic renal failure
coronary heart disease
diabetes
osteoporosis
parkinson’s disease
stroke

Question 14

What are the different approaches to CNS drug discovery?

Answer 14

1. pathology to drug
2. Reverse translation

Question 15

Describe ‘pathology to drug’ approach in CNS drug discovery.

Answer 15

Analysis of disease pathophysiology results in identification of novel disease pathways

1. selection of novel drug targets and parellel development of disease relevant models for screening
2. select drug candidates

Question 16

What factors/properties of a cell leads to disease?

Answer 16

growth
shape
differentiation
movement
division
apoptosis
metabolism
scretion
excitability

Question 17

What factors/properties of tissue leads to disease?

Answer 17

growth
atrophy
repair
inflammation
infection
ischaemia
necrosis

Question 18

List some ‘malfunctions’ of physiological systems

Answer 18

Hypoxia
hyperglycaemia
hypertension
heart failure
renal failure
epilepsy
hemiplegia
obesity

Question 19

Describe the ‘pathology to drug’ approach in CNS drug discovery.

Answer 19

Analysis of disease pathophysiology results in the identification of novel disease pathways.

–> select over drug targets and develop disease models

Question 20

Describe the ‘reverse translation’ approach in CNS drug discovery.

Answer 20

understanding current pharmacotherapy to
identify the mechanism of action and
develop animal models to screen for compounds

–> drug candidates similar properties as existing drugs

Question 21

Prozac is an antidepressant of which class?

Answer 21

selective serotonin reuptake inhibitor (SSRI) class

Question 22

What is 5-HT?

Answer 22

serotonin

Question 23

What are the 2 paradigms in target discovery?

Answer 23

1. physiology-based approach
2. target-based approach

Question 24

Briefly explain the physiological approach in drug discovery

Answer 24

• Follows physiological readouts
• Drug targets and the mechanism of action would be deduced later based on specific pharmacological properties.

Question 25

Briefly explain the 'target-based approach' in drug discovery

Answer 25

1. identify possible therapeutic target and its role in disease

Question 26

What has been the main driver of 'target-based approach'?

Answer 26

genomics revolution

Question 27

What are the main families of proteins known to be likely drug targets?

Answer 27

G protein-coupled receptors (GPCRs) kinases proteases --> acheiving selectivity for just one member of such a family can be challenging

Question 28

Give some examples of drug targets

Answer 28

1. ion channels 2. enzyme inhibitor 3. GPCR 4. transmembrane agonist

Question 29

What is a transmembrane agonist?

Answer 29

a type of ligand or molecule that binds to a receptor located on the cell membrane and triggers a cellular response or activation.

Question 30

How are novel endogenous ligands for orphan receptors (such as GPCRs) discovered?

Answer 30

1. transfection --> expression of receptor in heterologous cells 2. second messenger --> observe changes in second messenger levels 3. tissue extraction (expected to contain the transmitter) --> tested for their ability to activate orphan receptor 4. fractionation --> activitites of fractions monitored 5. isolations and structure determination

Question 31

What is a druggable target?

Answer 31

Generally, a druggable target is a protein or other functional biomacromolecule whose activity can be modulated by ligands with drug-like properties.

Question 32

What is the role of biologists in drug discovery process?

Answer 32

discover gene products whose activity can be modulated by high-affinity ligands

Question 33

What is the role of medicinal chemists in drug discovery process?

Answer 33

responsible for dispensing drug-like structural and physicochemical properties to 'hits' and 'leads'

Question 34

What is the role of pharmacologists in drug discovery process?

Answer 34

ensure clinical candidates are active and safe

Question 35

What is the role of clinicians in drug discovery process?

Answer 35

ensure drug candidates are efficaceous, useful and safe

Question 36

What are some factors that may affect the druggability of a target?

Answer 36

1. Cellular location --> central vs perpheral; cell surface vs intracellular 2. Development of resistance and tolerance --> analgesics: drug addiction 3. transport mechanisms --> penetration through blood brain barrier 4. side effects --> affect productivity 5. toxicity --> not a major concern in life-threating conditions

Question 37

The disparity between the number of transmitters to be matched and the much larger number of orphan GPCRs led to the hypothesis that many transmitters remain to be discovered. True or False.

Answer 37

True

Question 38

How many 'druggable' targets in human genome?

Answer 38

600-1500

Question 39

Targets for therapeutic intervention can be broadly categorized as:

Answer 39

◼ Receptors  Intracellular receptors  Cell surface receptors ◼ Proteins and enzymes ◼ DNA, RNA, and ribosomal targets

Question 40

What is genome?

Answer 40

the complete genetic makeup (the entire DNA complement) of the organism