Lecture 2 Flashcards
What is drug discovery?
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.
Name some environmental influences that lead to diseases.
- long-term phenotype changes sucg as weight gain, muscle weakness or depression
- stressful environment
- smoking (initiated as a result of social factors)
What does exposure to stressful environment lead to?
activate hypothalamopituitary system and therby increase adrenal steroid secretion, which affects:
- gene transcription in cells and tissues
- salt metabolism
- immune responses
The increase in adrenal steroid secretion affects:
- gene transcription in cells and tissues
- salt metabolism
- immune responses
What are some of the issues with current drug discovery process?
- long time between initial conception and final marketing
- high attrition rate: 1 out of 5000 compound
- costly process
What are some potential ways to improve drug discovery process?
- identify and validate more targets in a faster pace
- eliminate problematic candidates earlier to reduce costs
- enable targeted therapeutics
What is the choice of therapeutic area often based on?
- Available expertise and technology
- Patent positions
- Pharmaeconomics
- Unmet medical need
- Potential market size and patient population
- Existing competition and market dominance
Define orphan drug
a pharmaceutical agent that has been developed specifically to treat a rare medical condition (an orphan disease) that inflicts less than 200,000.
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
True
How do orphan drug regulations assist in the development of orphan drugs as it may have poor pharmaeconomics?
- fewer patients can be tested for phase III clinical trials as it is an orphan disease
What interventions are provided by the gpvernment on behalf of orphan drug development?
- tax inxentives
- enhanced patent protection and marketing rights
- clinical research financial subsidization
- creating gov’t run enterprise to engage in research and development
Name an orphan disease
Blepharospams
-Overactive blinking, eventually leading to the inability to open the eye lids and thus
blindness
-treated with Botox (botulinium toxin type A)
List some age-related diseases
Alzheimer’s disease
Cancer
Chronic renal failure
coronary heart disease
diabetes
osteoporosis
parkinson’s disease
stroke
What are the different approaches to CNS drug discovery?
- pathology to drug
- Reverse translation
Describe ‘pathology to drug’ approach in CNS drug discovery.
Analysis of disease pathiophysiology results in identification of novel disease pathways
- selection of novel drug targets and parellel development of disease relevant models for screening
- select drug candidates
What factors/properties of a cell leads to disease?
growth
shape
differentiation
movement
division
apoptosis
metabolism
scretion
excitability
What factors/properties of tissue leads to disease?
growth
atrophy
repair
inflammation
infection
ischaemia
necrosis
List some ‘malfunctions’ of physiological systems
Hypoxia
hyperglycaemia
hypertension
heart failure
renal failure
epilepsy
hemiplegia
obesity
Describe the ‘pathology to drug’ approach in CNS drug discovery.
Analysis of disease pathophysiology results in the identification of novel disease pathways.
–> select over drug targets and develop disease models
Describe the ‘reverse translation’ approach in CNS drug discovery.
understanding current pharmacotherapy to
identify the mechanism of action and
develop animal models to screen for compounds
–> drug candidates similar properties as existing drugs
Prozac is an antidepressant of which class?
selective serotonin reuptake inhibitor (SSRI) class
What is 5-HT?
serotonin
What are the 2 paradigms in target discovery?
- physiology-based approach
- target-based approach
Briefly explain the physiological approach in drug discovery
- Follows physiological readouts
- Drug targets and the mechanism of action would be deduced later based on specific pharmacological properties.
Briefly explain the ‘target-based approach’ in drug discovery
- identify possible therapeutic target and its role in disease
What has been the main driver of ‘target-based approach’?
genomics revolution
What are the main families of proteins known to be likely drug targets?
G protein-coupled receptors (GPCRs)
kinases
proteases
–> acheiving selectivity for just one member of such a family can be challenging
Give some examples of drug targets
- ion channels
- enzyme inhibitor
- GPCR
- transmembrane agonist
What is a transmembrane agonist?
a type of ligand or molecule that binds to a receptor located on the cell membrane and triggers a cellular response or activation.
How are novel endogenous ligands for orphan receptors (such as GPCRs) discovered?
- transfection
–> expression of receptor in heterologous cells - second messenger
–> observe changes in second messenger levels - tissue extraction (expected to contain the transmitter)
–> tested for their ability to activate orphan receptor - fractionation
–> activitites of fractions monitored - isolations and structure determination
What is a druggable target?
Generally, a druggable target is a protein or other functional biomacromolecule whose activity can be modulated by ligands with drug-like properties.
What is the role of biologists in drug discovery process?
discover gene products whose activity can be modulated by high-affinity ligands
What is the role of medicinal chemists in drug discovery process?
responsible for dispensing drug-like structural and physicochemical properties to ‘hits’ and ‘leads’
What is the role of pharmacologists in drug discovery process?
ensure clinical candidates are active and safe
What is the role of clinicians in drug discovery process?
ensure drug candidates are efficaceous, useful and safe
What are some factors that may affect the druggability of a target?
- Cellular location
–> central vs perpheral; cell surface vs intracellular - Development of resistance and tolerance
–> analgesics: drug addiction - transport mechanisms
–> penetration through blood brain barrier - side effects
–> affect productivity - toxicity
–> not a major concern in life-threating conditions
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.
True
