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PHAR 300 > Drug design 1 > Flashcards

Drug design 1 Flashcards

1
Q

What is evidence based medicine

A

Need to base on evidence
Alllowd to have drug to increase longevity and lifestyle

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2
Q

What is needed - evidence aspects

A

Does it work
What are the side effects
How does it compare to what is available - has to be as good as what on market

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3
Q

How can drugs get to market

A

If positives outweighs negatives

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4
Q

Biggest causes of death in canada

A

Cancer and heart disease

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5
Q

Describe major changes in causes of death

A

Lifespan has doubled over past century= huge differences in sanitation, immunization and antibodies = huge differences in death Rates
Alzheimer’s disease = prevalent
Cancer and heart disease = current emphasis

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6
Q

What is the future of drug discovery

A

Personalized therapy - analyze genetic makeup
Drugs - antibodies, cytokines, cells
New treatments for cancers = Ned to type tumours in pop = tailor therapies

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7
Q

Describe drug discovery generally

A

Basic = from lab to final drug trials to patients
Research = figure our fundamental problems in diseases and what we can do about it

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8
Q

Describe research spending sales

A

Much on pharmaceuticals = expensive
Easier targets have been explore so now = harder, more complicated issues

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9
Q

Describe biological drugs

A

From living organisms/cellls
Increasing use of biologics
Types of drugs developed = changing

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10
Q

What are top selling drugs

A

More than half of drugs = monoclonal antibodies

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11
Q

Describe disease categories with new drugs approved in 2023

A

Infectious diasease = Viruses - also resistance to antibioyoic drugs
Neurology = disorder, Parkinson’s, alxeihmers
Oncology = highest

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12
Q

What structures of drugs approved in 2023

A

Oligonucletodes
Proteins
Small molecules

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13
Q

Describe developing a novel drug

A

Time = 14years Avg, 10 yers to get to patent
Money = up to 2 billion euro, 2.4 billlion us
Human Resources = 150 researchers
2023 = top 20 companies spent 145 billion on r&d, global total = 260-300 billion

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14
Q

When is greatest cost of drug dev

A

Clinical trials = in humans

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15
Q

Describe survival rates for childhood cancers

A

Almost all children survive now
Very good

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16
Q

Describe Alzheimer’s

A

Neurological
Many osiers
Do not understand what goes wrong
Amyloid plaques
Many drugs tested but none work

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17
Q

Describe Eli Lilly drug Alzheimer’s

A

2016 results = more than 1 billion spent on new drug for Alzheimer’s
Tested in humans = not better than placebo

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18
Q

Describe new Alzheimer’s drug 2021

A

Alzheimer’s due to amyloid plaques - why accumulate = don’t know
Antibodies to stop plaque formation
Aducanumab = targeting Alzheimer’s disease pathology
Not approved in Canada, small benefit if any, v expensive

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19
Q

Describe dementia drugs

A

Inhibit acetylcholinesterase
Inhibit NMda receptor
Amyloid antibody
Got through testing but no more than brief middle benefit

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20
Q

Describe antibiotic issues

A

New systemic antibacterial agents approved by fda = not many
Not cost effective
Decline in research bc not getting money back - since antibodies taken for short amount of time
But antibiotic resistance…

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21
Q

Describe phases of drug dev

A

Idea and preclinical research
Involves pharmacology and toxicology
5.8 years
Work out targets, structures, all effects, test in animals, toxicology and pharmacology

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22
Q

Describe major challenges in health care

A

Chronic diseases we need to cure or prevent = Parkinson’s, Alzheimer’s, arthritis
Common killers to prevent/cure = cancer, cardiovascular = mi and stroke
Global concerns = emergening ifnections - understand them, help deal with ppl suffering from effects of pollution

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23
Q

How to deal with major challenges in healthy care

A

= require basic resreahc

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24
Q

Describe gov/industry

A

Gov + unit reasearch labs, gov funded = do most basic research, translational research and some clinical reasearch
Pharm companies = do most clinical and translation, less basic

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25
Q

How to develop drugs - first step

A

Understanding pathogenesis

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26
Q

Describe pathognesis of coronary artery desiease

A

Plaque builds up
Clot or plaque occludes = heart wall
Big killer, but not much rearech = know much about it, must make lifestyle changed = best way to treat, but don’t know much about cancer

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27
Q

Describe drug targets

A

Active site of enzyme in microbe, any microbial vulnerability
Any functional competent of a cell —> manu receptors, must figure out which involved inpathognesis

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28
Q

Why do drugs targets fail

A

Many things react = inter communication between levels, modifications, control pathways
Reasons for failure = multiple control pathways interact

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29
Q

How many drug targets

A

~500 proteins are current targets, but 10 000 targets in genome - as understand more
About disease genetics = help understand what most useful clinical targets are
Also selecting responders = genetics based selection of optimal population, people that will response the best

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30
Q

What are genomics

A

Important
Slowly progressing, no miracles

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31
Q

Describe functional genoemes

A

Understanding the function of a gene or its variants = understand variability
—> target validation = finding suitable drug targets, related to gene function
—>improved pace and extend of drug dev
Ex= pro state cancer, genetic changes in tumour not the same from one person to next

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32
Q

Describe gene therapy

A

Vector carrying new gene inserted into cell
Gene therapy
Know abnormality = many attempts to deliver/replace missing gene, not co,plate successes

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33
Q

Describe worlds first gene therapy

A

Crisper based treatment of sickle cell and thalassemia
Rbcs distorted due to abnormal hemoglobin gene
Take stem cells out and treate in lab = correct gene then give stem cells to patients = repair hb genes

34
Q

Describe genetic differneces

A

Most diseases have >1 genetic abornamilty
Gene polymorphisms = complicated
Look at pharmacokinetics and dynamics

35
Q

What does underfunding pathogeneiss do

A

Analyze patient profile and see which problem patient has, complicated tho

36
Q

Describe pregenomics

A

Disease description
Uniform disease
Patient homogeneity
Universal therapeutic stragety

37
Q

Describe genomics- after genomics

A

Disease mechanism - know that everyone diff
Disease heterogeneity = can subtype category
Address individual varianton
Patient risk profiling, pharmacogenomics and targeted care = target therapy to patients variation

38
Q

Why measure gene expression

A

Response to stimuli = environmental changes like drugs or disease often cause changes in expression
Disease makers and drug targets = changes in expression associated with disease can be diagnostic makers and/or suggest novel pharmaceutical approaches = try to come up with better drug targets

39
Q

Describe bioinformatics

A

Reasearch
Allows huge amounts of computation to take place can target specifically abnormalities
Diagnostic, prognostic
New molecular atgerets based on better preclinical dev and understanding of disease - by bio marker analysis for clinical trials (individuals)

40
Q

How to find target ligand

A

Something that will blind and block it
Have models of enzyme then come up with model o drug that fits active site
Enzyme - drug blocking zneyme
Design drug candidates based on this

41
Q

Combinatorial chemistry describe

A

Play arounf with structures
Creation of compound libraries —> biological screening - use better ones to model and eventually come up with best option, 5000-10 000 drugs —> eventallly get new drug

42
Q

Describe combinatorial chemistry within drug design

A

Therapeutic target —> lead discovery, compounds that binds to target —> lead optimization- by creating sctructural derivatives, should be more and more effective with less side effects —> development candidate —> drug
Many variations of each section the combine
10000 compounds

43
Q

How to test componds

A

Robotics = high throughput screening
Thousands of compounds at a time

44
Q

Describe Manual tenciques - antibiotic producers

A

Put in plate and test each
Evaporate test, isolate antibiotic produces, determination fo antibiotic spectrum of activity

45
Q

What makes testing chemical easier

A

High throuput screening
Robotics + bioinformatics = 20 000 compounds / day
Look for agonists or antagonists of target
Expensive and sophisatcated but efficient

46
Q

Describe test systems

A

Mammalian cells
Microbes
Human
Specific cells
Hepatocytes
Microsomes - subcellular fractions
Synthesis membranes
Beads

47
Q

Name and describe 2 general types of high throughput screens

A

Cell free = ligand recpcetor interactio, ex = enzyme in wells
Cell based - multiple targets in chambers

48
Q

How to quantify

A

Fluorescence
Luminescence
Enzymatic
Radioactive
Immunological

49
Q

What does high throughput molecular analyze require - 4

A

Suitable compound libraries
Automatic assay method configured for automation
Robotics workstation
Computerize system capable of handling data - analyzeing

50
Q

Describe process of high throughput screening

A

Wells have compounds up to 10 000 diff wells
Labelled anybody will bind to tangent
Luciferase = will glow

51
Q

Describe reporter gene assay

A

Luciferase mRNA reseigned to target
Toxin to drug
Detect target gene expression

52
Q

Describe automated ligand identification system

A

Target protein
Put it in system with mixture of proteins
Then washe out = protein and bound compounds separated from unbound componds
Chromatography releases bound compound from protein - only a few things bound - relase bound proteins then
Compound masss measured by mass spec - data analysis system - correlates mass data with list of compound masses
Identifying structure of bound compound - proteins that bind

53
Q

Describe zebra fish

A

Can use living thing
Ex = fluorescent labelling
Many diff labels
Maybee useful in treatment of cancer = test candidates using rapid trans genesis
Look at many things, further study in other creatures, cancer imaging - juveniles and adult cancer models

54
Q

What can high throuput screening not evaluate

A

Bioloaviabelity = like how much will get through liver
Pharmacokinetics
Toxicity
Mutagenicity
Speciifcity = will not know where else it will have effects, needs to be determined in living system

55
Q

Describe mutagen monitor

A

Yeast celll - with dna repair gene And jelly fish gene produces flo protein whenever dna repair gene activated
If dna repair genes altered = can test
Bright green glow reveals possible carcinogens
Test chemical using this
Can test if will block mobility of cancer cells - can treat cancer, since cannot mestatsize

56
Q

Describe automated assays for toxicants

A

Important
Looking at air we breathe

57
Q

Describe publications and data banks

A

Increasing

58
Q

What is bioinformatics

A

General and handle vast amounts of biological data
Algorithmic
Generation of understand
From vast amounts of
Molecular biological data

59
Q

Describe how computational chemistry works

A

Work out how to develop a enter drug
More effective
Look at receptor bindings site, oral diabetes drugs, free fatty acid r

60
Q

What can computeational chemistry software do

A

Software uses Knowldge of enzyme to design new frugs, knows structure of it and now designed new drug - combinatorial chemistry will make it
Can predict structure of complex, including correct conformation that will bind best to active site on enzyme
Result takes about a minute
Can also model hydrophobicuty = new interaction geometries for hydrophobic interactions

61
Q

Describe hiv protease inhibitor

A

Computer aided drug design
Most of recent ones =developed by computer

62
Q

What is steps of computer designengd rug

A
  1. Drug deisgn target = hiv protease, viral enzyme
  2. Generator molecular surface for active site, software
  3. Active site-ligand model
  4. Another view with potential ligand in active site and see how binds
63
Q

Describe new cancer drug

A

Ibrutinib blocks enzyme overexpressed in B cell malignancies - approved in 2014
V good, few side effects
Cancer = chronic lymphocyte leukaemia

64
Q

Describe heart debase drugs

A

Blocks enzyme that lowers ldl receptor = unhealthy type
= stratgeuty to increase removable of it
Before = statin inhibits cholesterol synthesis = good
Now = allows liver to take more of Ldl out of circulation = inhibition of pcsk9 enhances removal ldl-c
More cholesterol removed

65
Q

Describe bridge between genomes and combinatorial CHEM and bioinformatics

A

Super compression of drug discovery
Decrease time it takes preclincially

66
Q

What is bio simulation

A

Computer aided mathematical simulation of biological processses and systems
Know more about general biology of human = can predict side effects
Increasing used to predict pos and neg, get ride of toxic/bad side effects ahead of time = before clinical testing

67
Q

Describe strategies to avoid formation of anti mouse antibodies

A

Chimeric antibodies = mouse variable region + human constant region
Primatized antibodies = chimeric with primate derived variable region
Huamnzied antibodies = all human except antigen recognition site
Transgenic mouse antibodies = fully humanize antibody

68
Q

Describe what monoclonal antibodies can treat

A

Autoimmune disorder = crohns, rheumatoid arthritis
Cancer = B cell malignancies, breast cancer
Osteoporosis = antibodies against osteoclasts, v effective

69
Q

Describe treatment of osteoporosis

A

Prevent or tretae so no fractures
Always turning over bones
Denosumab
Blocks osteoclasts = keep at equilibrium, effective drug
But if old = vulnerable to issues, less strength in bone

70
Q

Describe breast cancer treatment

A

Mponoloclinal antibodies targeting her2 protein overexpressing cell

71
Q

Describe treatment colorectal cancer

A

Many potential targets

72
Q

What is Adalimumab

A

Inhibition for autoimmune diseases
Inhibiting pathogenic molecule involved in autoimmune diseases, like arithristis

73
Q

Wat is great for arthritis this

A

Remicade

74
Q

What is preclinical eval

A

After work in lab
Lab rats
Investigate in cells then in tissues
animals
Can make transgenic and ko mice
Detailed mechanism of action studies, in rodents, very useful for humans

75
Q

What can lab rats help us figure out

A

Pharmacokinetics
Similar to what humans do
Want to detect toxicity in advance -
Acute and chronic toxicity

76
Q

What animals can be used to test

A

Rabbits
Cattle/horses
Dogs
Cats
Rats/mice = most common
Primates = some types of studies = gynaecology, biologicals, toxicology

77
Q

What is Ames test

A

Look for mutants
Carcinogens and teratogens

78
Q

What must we test - drug process whole

A

Find a target = a naturally occurring molecule to be enhanced or inhibited, must understand pathogenesis of disorder
Find a lead = drug like molecule that interacts specifically with target
Optimize = find a compound in same fam as lead that is specific and effective enough to be drug
Work our ADMET = absorption, distribution, metabolism, excretion and toxicity
May have to go around circle manny times

79
Q

What does drug need to be

A

Safe and effective drug
Need convincing evidence then apply to gov for approval to test in humans

80
Q

Describe newer areas of dev and testing

A

Golden rule = newer concept of vitamin - drug, provision
Change plant to have vitamin = help kids not be vitamin deficient

81
Q

What will we test in clinical trails

A

Is it safe
Does it work
Things will change in future

PHAR 300 (22 decks)

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