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Week 1 Part 1 Flashcards

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1
Q

Developing a new drug from original idea to launch a finished product takes how many years?

A

12-15 years

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2
Q

What is the cost of making a drug?

A

Excess of 1 billion dollars

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3
Q

Where can idea of a target come from?

A

Academic and clinical research

Commercial sector

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4
Q

Why does a drug discovery programme initiate?

A

Disease/clinical condition without suitable medical procedure available

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5
Q

Where does initial research happen?

A

In academia
Generates data to develop hypothesis that inhibition/activation of a protein/pathway will result in a therapeutic effect in a disease state

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6
Q

What is the outcome of activity?

A

selection of a target which may require further validation to go into lead discovery phase in order to justify a drug discovery effort

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7
Q

What is lead discovery?

A

Intensive research
Find a drug-like small molecule or biological therapeutic
This progresses into preclinical and if successful —> clinical development
Finally be a marketed medicine

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8
Q

Why does drug fail?

A

They do not work

They are not safe

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9
Q

What is an important step in developing a new drug?

A

Target identification and validation

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10
Q

What is the definition of a target?

A

Broad term
Applied to a range of biological entities
E.g. proteins, genes, RNA

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11
Q

What does a good target need to be?

A

Efficacious
Safe
Meet clinical and commercial needs
Be druggable

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12
Q

What is a druggable target accessible to?

A

Putative drug molecule
Be a small molecule or a lager biological
Upon binding, elicit a biological response
Measured both in vitro and in vivo

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13
Q

What does a good target identification and validation enable?

A

Increases confidence in relation between target and disease

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14
Q

Increased target identification

A

Data mining of available biomedical data
Use of bioinformatics approach - selecting and prioritising potential disease targets
Include publication and patent information

Gene expression data
Transgenic phenotyping
Compound profiling data

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15
Q

Look for genetic associations

A

Is there a link between genetic polymorphism and risk of disease

Is the polymorphism functional ?

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16
Q

What is an example of phenotypes in human where mutation can nullify or over activate the receptor?

A

Voltage-gated sodium channel Nav1.7

Incur a pain phenotype
Insensitivity or oversensitivity

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17
Q

What do you use phenotypic screening for?

A

Identify disease relevant targets in

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18
Q

Target validation

A

Once identified, the target needs to be fully prosecuted

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19
Q

What is the technique for target validation?

A

In-vitro tools through use of animal models

Modulation of a desired target in disease patients

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20
Q

What is Anti-sense technology?

A

Use RNA-like chemically modifies oligonucleotide that is complementary to region of target MRNA molecule

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21
Q

What does binding of antisense oligonucleotide + target MRNA prevent?

A

Binding of translational machinery

Blocking synthesis of encoded proteins

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22
Q

Transgenic animal for target validation

A

Involves whole animal
Allows the observation of phenotypic endpoint to explain the functional consequence of gene manipulation

Use of transgenic animal is expensive and time consuming

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23
Q

The use of small interfering RNA (siRNA) for target validation

A

Short double stranded fragments
SiRNA are then separated into single strands
Integrated into an active RNA induced silencing complex (RISC)
After integration, siRNA base-pair to their target MRNA and induce cleavage of MRNA
Prevent it from being used as a translation template

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24
Q

Monoclonal antibodies for target validation

A

Interact with a larger region of target molecule surface

Allows for a better discrimination between closely related targets

Provide higher affinity

Can be selected to bind unique epitopes

Example of efficacy of mAb in vivo - function neutralising anti-TrkA antibody MNAC13 - reduce both neuropathic pain and inflammatory hypersensitivity

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25
What is a classic target validation tool?
Small bioactive molecule that interacts with and functionally modulates effector protein
26
Chemical genomics of target validation?
Study of genomic responses to chemical compounds Goal: rapid identification of novel drugs Brings together diversity-oriented chemical libraries and high information content cellular assays along with informatics and lining tools necessary for storing and analysing data generated
27
What can be developed during hit identification and lead discovery phase of drug discovery process?
Compound screening assays
28
Definition of hit molecule
Compound which has desired activity in compound screen and whose activity is confirmed upon retesting
29
What are examples of screening paradigms that exist for hit molecule?
``` High throughout screening (HTS) Focused or knowledge-based screening Pharmacores and molecular modelling Fragment screening Tissue based approach ```
30
High-throughput screening
Screening of entire compound library directly against the drug target Or in a more complex assay system (cell based assay) Whose activity is dependent upon target
31
What do you observe in a HTS?
Observe purified protein which are the target and put HTS that may have potential characteristic of interest
32
Setting up HTS
Compounds may be derived from medicinal chemistry and SAR | Or large pharmaceutical companies
33
What is the purpose of HTS?
Identify through a robust reproducible assay a drug/compound that may be of interest
34
What is usually preferred in HTS?
Fluorescence based assay in terms of how quickly they can give you results on a time-scale basis
35
What is a lot of HTS ?
Automated
36
Massive array set hon
Whereby assay solution can repeated many times with all of these different compounds
37
6 months after HTS
Move into a process where it is identified as hits
38
Filter down compounds - look for one that actually produced a desired effect
Look at affinity for compound for a receptor | Generate dose-response curves
39
What is focused or knowledge based screening?
Selecting from chemical library smaller subsets of molecules that are likely to have activity at target protein Based on the knowledge of target protein and literature or patent precedent for chemical classes
40
What is pharma core and molecular modelling?
Virtual screens of compound data base
41
What is fragment screening?
Generation of very small molecular compound libraries Screened at high concentration Accompanied by the generation of protein structure to enable compound progression
42
What is tissue-based approach?
Looks for a response more aligned with final desired in-vivo effect
43
G protein coupled receptors
It is very unlikely that only one receptor is causing all of the symptoms When ligand + GPCR = conformational change - act as a guanine nucleotide exchange factor (GEF) The GPCR can activate G protein by exchanging the GDP bound for a GTP The G proteins alpha subunit together with the bound GTP can dissociate from beta and gamma subunit to further affect intracellular signalling proteins
44
Fluorescent imaging plate reader (FlipR) assay
Fast and easy method for detecting activation through changes in intracellular calcium concentration Instrument which are used to detect biological, chemical or physical events of a sample in microtiter
45
What does coupling receptors to Gq protein stimulate?
Inatracellular calcium flux upon binding | Functional response: calcium-sensitive due and fluorescence plate reader
46
Fluo-3 dye Ester is loaded into cell and cleaved by?
Cell esterases to activate dye
47
What does Fluo-3 result in?
Increased fluorescent emission at 520nm
48
What is amenable for High throughput?
Grow your own cells | Functional assay
49
High throughout tells you nothing about
How the receptor will operate in a native environment
50
What is lead discovery phase?
Development of biological assay | Identification of molecules with activity at drug target
51
Where has cell based assays been applied to?
Membrane receptors Ion channels Nuclear receptors Generate functional readout as a consequence of compound activity
52
What is biochemical assay
Applied to both receptor and enzyme target Measure affinity of test compound for target protein Used to identify hit and candidate molecules
53
What is the choice of assay formation?
Dependent on biology of drug target protein Equipment infrastructure The experience of the scientist Whether an inhibitor or activator molecule Is sought for scale of the compound screen
54
What are requirements for | Assay format?
``` Pharmacological relevance of assay Reproducibility of assay Assay cost Assay quality Effects of compound in the assay ```
55
What is assay capable of identifying?
Compounds with the desired potency and mechanism of action
56
Pharmacological relevance of assay
Determine whether assay pharmacology is predictive of disease state
57
Assay cost
Compound screening assay performed in microtitre plates Academia: performed in 96-well or 384-well Industry: formatted in 384-well or 1536-well microtitre
58
Assay quality
Determined according to Z’ factor Statistical parameter - consider signal window in assay Considers the variance around both Hugh and low signals in the assay
59
What is Z factor?
Standard means of measuring assay quality on a plate bases | Ranged from 0 to 1
60
Assay with a Z factor greater than > 0.4
Robust for compound screening
61
Many groups prefer to work with assays with a Z factor...
> 0.6
62
Effects of compound in the assay
Cell-based assays are intolerant to solvent concentration of greater than 1% DMSO Biochemical assays can be performed in solvent concentration of up to 10% DMSO
63
What is the compound concentration for hit discovery ?
Run at 1-10 mM
64
Compound libraries contain small molecular weight molecules that obey chemical parameters such as
Lipinski rule of 5
65
What is clogP?
Measure it lipophilicity which affects absorption into the body Molecules with these features are “drug-like”
66
Clinically marketed drugs
Molecular weight of less than 350 and a clogP of < 3
67
Why is it important to initiate drug programme with small simple molecule?
Lead optimisation | Improve potency and selectivity
68
What is the first and second step in initial refinement process?
1: compounds known by library curator removed from further consideration 2: generate a dose-response curve in the primary assay for each hit
69
Why are reversible compounds favoured?
Their effects can be more easily ‘washed-out’ following a drug withdrawal
70
What is lead series?
Medicinal chemists would look to cluster compounds into groups
71
Hit-to-lead phase
Refine each hit series Produce more potent and selective compound which possess PK properties Examine efficacy in any in-vivo models that are available Involves intensive SAR investigations around each core compound structure Measurements made to establish magnitude of activity and selectivity of compound Carrie our systemically Structural information about target is known
72
What is solubility and permeability assessments crucial for?
Rule in and out the potential of a compound to be a drug
73
What is a formulation strategy?
Design a tablet such that it dissolves in a particular region of the gut at a PH in which the compound is more soluble
74
What is 5-hydroxytryptamine (5-HT)?
Group of GPCR and ligand gayer ion channel found in CNS and PNS Mediate both excitatory and inhibitory neurotransmissiojn
75
5-HT3
Ligand-gated Na+ and K+ cation channel Depolarising plasma membrane Excitatory
76
What is SOC criteria?
Biological activity Sample integrity Potential to optimise Assay availability
77
What can lead molecule be?
Optimised | Turned into a potential drug
78
What is lead optimisation phase?
Maintain favourable properties in lead compounds Improve on deficiencies in lead structure Compounds at this stage may have met initial goals of Lead optimisation phase ready for final characterisation before declared as preclinical candidate Team continue to explore synthetically in order to produce potential back up incase compound fails
79
Once a candidate is reached, the attrition rate of compound entering the clinical phase is high
Only 1 in 10 candidates reach the market
80
Once a candidate reaches clinical | Stage, it becomes increasingly difficult to kill the project, why?
At this stage the project has become public knowledge and thus termination can influence confidence in the company and shareholder value
81
What may help in this endeavour
Carry more studies - improved toxicology screens Establish predictive translational models based on a thorough disease understanding Identifying biomarkers
82
What is calcium imaging?
Show calcium status of an isolated cells, tissue or medium

DDD x (17 decks)

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