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DDD x > Week 1 Part 1 > Flashcards

Week 1 Part 1 Flashcards

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
Q

What is a classic target validation tool?

A

Small bioactive molecule that interacts with and functionally modulates effector protein

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26
Q

Chemical genomics of target validation?

A

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

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27
Q

What can be developed during hit identification and lead discovery phase of drug discovery process?

A

Compound screening assays

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28
Q

Definition of hit molecule

A

Compound which has desired activity in compound screen and whose activity is confirmed upon retesting

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29
Q

What are examples of screening paradigms that exist for hit molecule?

A 
High throughout screening (HTS)
Focused or knowledge-based screening 
Pharmacores and molecular modelling
Fragment screening 
Tissue based approach
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30
Q

High-throughput screening

A

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

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31
Q

What do you observe in a HTS?

A

Observe purified protein which are the target and put HTS that may have potential characteristic of interest

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32
Q

Setting up HTS

A

Compounds may be derived from medicinal chemistry and SAR

Or large pharmaceutical companies

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33
Q

What is the purpose of HTS?

A

Identify through a robust reproducible assay a drug/compound that may be of interest

34
Q

What is usually preferred in HTS?

A

Fluorescence based assay in terms of how quickly they can give you results on a time-scale basis

35
Q

What is a lot of HTS ?

A

Automated

36
Q

Massive array set hon

A

Whereby assay solution can repeated many times with all of these different compounds

37
Q

6 months after HTS

A

Move into a process where it is identified as hits

38
Q

Filter down compounds - look for one that actually produced a desired effect

A

Look at affinity for compound for a receptor

Generate dose-response curves

39
Q

What is focused or knowledge based screening?

A

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
Q

What is pharma core and molecular modelling?

A

Virtual screens of compound data base

41
Q

What is fragment screening?

A

Generation of very small molecular compound libraries

Screened at high concentration

Accompanied by the generation of protein structure to enable compound progression

42
Q

What is tissue-based approach?

A

Looks for a response more aligned with final desired in-vivo effect

43
Q

G protein coupled receptors

A

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
Q

Fluorescent imaging plate reader (FlipR) assay

A

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
Q

What does coupling receptors to Gq protein stimulate?

A

Inatracellular calcium flux upon binding

Functional response: calcium-sensitive due and fluorescence plate reader

46
Q

Fluo-3 dye Ester is loaded into cell and cleaved by?

A

Cell esterases to activate dye

47
Q

What does Fluo-3 result in?

A

Increased fluorescent emission at 520nm

48
Q

What is amenable for High throughput?

A

Grow your own cells

Functional assay

49
Q

High throughout tells you nothing about

A

How the receptor will operate in a native environment

50
Q

What is lead discovery phase?

A

Development of biological assay

Identification of molecules with activity at drug target

51
Q

Where has cell based assays been applied to?

A

Membrane receptors
Ion channels
Nuclear receptors

Generate functional readout as a consequence of compound activity

52
Q

What is biochemical assay

A

Applied to both receptor and enzyme target
Measure affinity of test compound for target protein
Used to identify hit and candidate molecules

53
Q

What is the choice of assay formation?

A

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
Q

What are requirements for

Assay format?

A 
Pharmacological relevance of assay 
Reproducibility of assay 
Assay cost
Assay quality 
Effects of compound in the assay
55
Q

What is assay capable of identifying?

A

Compounds with the desired potency and mechanism of action

56
Q

Pharmacological relevance of assay

A

Determine whether assay pharmacology is predictive of disease state

57
Q

Assay cost

A

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
Q

Assay quality

A

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
Q

What is Z factor?

A

Standard means of measuring assay quality on a plate bases

Ranged from 0 to 1

60
Q

Assay with a Z factor greater than > 0.4

A

Robust for compound screening

61
Q

Many groups prefer to work with assays with a Z factor…

A

> 0.6

62
Q

Effects of compound in the assay

A

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
Q

What is the compound concentration for hit discovery ?

A

Run at 1-10 mM

64
Q

Compound libraries contain small molecular weight molecules that obey chemical parameters such as

A

Lipinski rule of 5

65
Q

What is clogP?

A

Measure it lipophilicity which affects absorption into the body

Molecules with these features are “drug-like”

66
Q

Clinically marketed drugs

A

Molecular weight of less than 350 and a clogP of < 3

67
Q

Why is it important to initiate drug programme with small simple molecule?

A

Lead optimisation

Improve potency and selectivity

68
Q

What is the first and second step in initial refinement process?

A

1: compounds known by library curator removed from further consideration
2: generate a dose-response curve in the primary assay for each hit

69
Q

Why are reversible compounds favoured?

A

Their effects can be more easily ‘washed-out’ following a drug withdrawal

70
Q

What is lead series?

A

Medicinal chemists would look to cluster compounds into groups

71
Q

Hit-to-lead phase

A

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
Q

What is solubility and permeability assessments crucial for?

A

Rule in and out the potential of a compound to be a drug

73
Q

What is a formulation strategy?

A

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
Q

What is 5-hydroxytryptamine (5-HT)?

A

Group of GPCR and ligand gayer ion
channel found in CNS and PNS

Mediate both excitatory and inhibitory neurotransmissiojn

75
Q

5-HT3

A

Ligand-gated Na+ and K+ cation channel

Depolarising plasma membrane

Excitatory

76
Q

What is SOC criteria?

A

Biological activity
Sample integrity
Potential to optimise
Assay availability

77
Q

What can lead molecule be?

A

Optimised

Turned into a potential drug

78
Q

What is lead optimisation phase?

A

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
Q

Once a candidate is reached, the attrition rate of compound entering the clinical phase is high

A

Only 1 in 10 candidates reach the market

80
Q

Once a candidate reaches clinical

Stage, it becomes increasingly difficult to kill the project, why?

A

At this stage the project has become public knowledge and thus termination can influence confidence in the company and shareholder value

81
Q

What may help in this endeavour

A

Carry more studies - improved toxicology screens
Establish predictive translational models based on a thorough disease understanding
Identifying biomarkers

82
Q

What is calcium imaging?

A

Show calcium status of an isolated cells, tissue or medium

DDD x (17 decks)

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