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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
How to develop drugs - first step
Understanding pathogenesis
26
Describe pathognesis of coronary artery desiease
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
27
Describe drug targets
Active site of enzyme in microbe, any microbial vulnerability Any functional competent of a cell —> manu receptors, must figure out which involved inpathognesis
28
Why do drugs targets fail
Many things react = inter communication between levels, modifications, control pathways Reasons for failure = multiple control pathways interact
29
How many drug targets
~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
30
What are genomics
Important Slowly progressing, no miracles
31
Describe functional genoemes
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
32
Describe gene therapy
Vector carrying new gene inserted into cell Gene therapy Know abnormality = many attempts to deliver/replace missing gene, not co,plate successes
33
Describe worlds first gene therapy
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
Describe genetic differneces
Most diseases have >1 genetic abornamilty Gene polymorphisms = complicated Look at pharmacokinetics and dynamics
35
What does underfunding pathogeneiss do
Analyze patient profile and see which problem patient has, complicated tho
36
Describe pregenomics
Disease description Uniform disease Patient homogeneity Universal therapeutic stragety
37
Describe genomics- after genomics
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
Why measure gene expression
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
Describe bioinformatics
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
How to find target ligand
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
Combinatorial chemistry describe
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
Describe combinatorial chemistry within drug design
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
How to test componds
Robotics = high throughput screening Thousands of compounds at a time
44
Describe Manual tenciques - antibiotic producers
Put in plate and test each Evaporate test, isolate antibiotic produces, determination fo antibiotic spectrum of activity
45
What makes testing chemical easier
High throuput screening Robotics + bioinformatics = 20 000 compounds / day Look for agonists or antagonists of target Expensive and sophisatcated but efficient
46
Describe test systems
Mammalian cells Microbes Human Specific cells Hepatocytes Microsomes - subcellular fractions Synthesis membranes Beads
47
Name and describe 2 general types of high throughput screens
Cell free = ligand recpcetor interactio, ex = enzyme in wells Cell based - multiple targets in chambers
48
How to quantify
Fluorescence Luminescence Enzymatic Radioactive Immunological
49
What does high throughput molecular analyze require - 4
Suitable compound libraries Automatic assay method configured for automation Robotics workstation Computerize system capable of handling data - analyzeing
50
Describe process of high throughput screening
Wells have compounds up to 10 000 diff wells Labelled anybody will bind to tangent Luciferase = will glow
51
Describe reporter gene assay
Luciferase mRNA reseigned to target Toxin to drug Detect target gene expression
52
Describe automated ligand identification system
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
Describe zebra fish
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
What can high throuput screening not evaluate
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
Describe mutagen monitor
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
Describe automated assays for toxicants
Important Looking at air we breathe
57
Describe publications and data banks
Increasing
58
What is bioinformatics
General and handle vast amounts of biological data Algorithmic Generation of understand From vast amounts of Molecular biological data
59
Describe how computational chemistry works
Work out how to develop a enter drug More effective Look at receptor bindings site, oral diabetes drugs, free fatty acid r
60
What can computeational chemistry software do
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
Describe hiv protease inhibitor
Computer aided drug design Most of recent ones =developed by computer
62
What is steps of computer designengd rug
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
Describe new cancer drug
Ibrutinib blocks enzyme overexpressed in B cell malignancies - approved in 2014 V good, few side effects Cancer = chronic lymphocyte leukaemia
64
Describe heart debase drugs
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
Describe bridge between genomes and combinatorial CHEM and bioinformatics
Super compression of drug discovery Decrease time it takes preclincially
66
What is bio simulation
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
Describe strategies to avoid formation of anti mouse antibodies
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
Describe what monoclonal antibodies can treat
Autoimmune disorder = crohns, rheumatoid arthritis Cancer = B cell malignancies, breast cancer Osteoporosis = antibodies against osteoclasts, v effective
69
Describe treatment of osteoporosis
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
Describe breast cancer treatment
Mponoloclinal antibodies targeting her2 protein overexpressing cell
71
Describe treatment colorectal cancer
Many potential targets
72
What is Adalimumab
Inhibition for autoimmune diseases Inhibiting pathogenic molecule involved in autoimmune diseases, like arithristis
73
Wat is great for arthritis this
Remicade
74
What is preclinical eval
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
What can lab rats help us figure out
Pharmacokinetics Similar to what humans do Want to detect toxicity in advance - Acute and chronic toxicity
76
What animals can be used to test
Rabbits Cattle/horses Dogs Cats Rats/mice = most common Primates = some types of studies = gynaecology, biologicals, toxicology
77
What is Ames test
Look for mutants Carcinogens and teratogens
78
What must we test - drug process whole
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
What does drug need to be
Safe and effective drug Need convincing evidence then apply to gov for approval to test in humans
80
Describe newer areas of dev and testing
Golden rule = newer concept of vitamin - drug, provision Change plant to have vitamin = help kids not be vitamin deficient
81
What will we test in clinical trails
Is it safe Does it work Things will change in future

PHAR 300 (22 decks)

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