L9 Dr. Greig: What separates the drug from the poison

Question 1

what are localized drugs and if they aren’t localized what could happen? Ex of Imodium

Answer 1

localized drugs are drugs that enter one region of the body and stay there to perform its role.

for instance, Imodium is a drug that is used for diarrhea and is localized to the gut

if imodium travels to the brain, it could actually be a poison and toxic as it would act as an addictive narcotic

Question 2

what is selectivity and why is it important

Answer 2

The selectivity of drugs = ability of a drug to bind selectively to a specific target or receptor in the body, while minimizing interactions with other non-target components.

selectivity is what separates the drug from the poison .. but not all drugs have this attribute

Question 3

what are the pros of simple drugs

Answer 3

since they are simple, they are inexpensive and can cure many sicknesses in your body. some are even selective (like aspirin) even though they are so generic.

Question 4

why are antibiotics revolutionary to other durgs

Answer 4

antibiotics are not only and control for bacterial infections, they also cure us from the bacterial infection

many other drugs just control the sickness we may have

antibiotics are truly lifesavers that we have been taking for granted

Question 5

what was a misconception in the 1990s about infections? and why was this wrong?

Answer 5

we believed that since we developed antibiotics the war on infections was won

however, we forgot about bacteria. we thought that pandemics were a thing of the past because not we have better surveillance and equipment

Question 6

what are two things we were told about their danger but did nothing about

Answer 6

• we have been told that antibiotics would grow resistant and the SARS is a dangerous virus (SARS covid-19) but we did nothing about changing our ways even when we were told this

Question 7

Tuberculosis (TB) is not a disease of the past. Explain why.

how many people have the disease,
how many people will further develop it?
will they live?
if we were administered drugs how would TB respond?

Answer 7

TB has killed 1 billion people in the last 200 years.

• up to 1/3 of the population has TB, but its just a latent disease in their body.
• but it is said that about 10% of people will develop the disease further and about 50% of them would die without treatment

if we were administered drugs how would TB respond?

drug sensitive TB
- 6 months of treatment
- cure rate 85%

multi-drug resistant TB
- 18 months of treatment
- 48% cure rate
- but 14000 pills and injections

extensively drug resistant TB
- no cure
- 34% cure rate

Question 8

when did we last develop a drug for antibiotics or TB

Answer 8

antibiotics 30-35 years ago
TB 60 years ago

Question 9

how do we separate the drug from the poison? (12)

Answer 9

• evolution
• millions of years
• a once in generation slice of luck (how the random impurity of a synthesis became an antibiotic)
• location (wont be toxic to the body if localized to a bacteria)
• very little changes to a cleverly engineered complex mechanism (ie. kinase)
• enough 3D complexity for selectivity
• lots of knowledge of our target (crystal structure)
• some desperation that our molecule is less toxic to our body than the target disease
• (sometimes) great or good potency
• try to synthesize the best drug so it stays in the body for a long period of time
• using the drug only as instructed
• a large therapeutic window

Question 10

why is it easy to create antibiotics?
why are we different to bacteria?
(separate drug from poison - billions of years)

Answer 10

we don’t have to worry about selectivity because antibiotics target bacteria and bacteria are very different to human cells in every way. This means that we have much different target physiology than bacteria.

so making antibiotics is easy because you don’t really have to worry about selectivity

why are we different to bacteria?
we have been diverging from them for several billion years. these compounds have also been engaging in chemical warfare, so they have space to grow on their own, thus helping us seperate the drug from poison.

Question 11

where did our antibiotics come from that make it difficult to make more again?

Answer 11

nature and screening.

we would take soil samples and find antibiotics, but these took 200 billion years to develop. we cant give nature that much time again and we have already looked through many soil samples. We also used them up so fast, thus causing resistance in a short period of time, thus limiting out ability to make new antibiotics.

Question 12

however, what is the main difficulty of making new antibiotics?

Answer 12

permeability, not selectivity

difficult for the antibiotic to go through the journey in the body.
we may use our typical method of making drugs (find targets and screen against chemical libraries, since we cant use natural antibiotics), but this may also lead to the creation of no drugs because of permeability.

the sorts of bioactive compounds that are able to go through the journey in the body are not drugs because they cannot infiltrate bacterium. only when they do are they considered a drug

Question 13

is it impossible for us to synthesise antibiotics in the same way as we would drugs for other diseases?

(separate drug from poison – sheer luck)

Answer 13

no, we were able to do it once, so surely we are able to do it again

this was once done with an impurity from the synthesis of chloroquine that had found its way into a screening library
this made the most potent broad spectrum antibiotic we have

Question 14

so what is the best approach to making antibiotics in this day and age?

Answer 14

maybe we need AI or computers to find compounds which will be active against bacterial targets, penetrate through their cell walls, and understand/discover a cool mechanism only used in that compound.

Question 15

Use the example of isoniazid for TB to explain how toxicity may be localized and thus not affect our health (separating drug from poison)

Answer 15

best ex. isoniazid for the treatment of TB
- it is absolutely nontoxic to the microbacteria
- it is antidepressant for depression

but when isoniazid gets in the microbacteria, it has an enzyme that defends itself against human immune system.
that same enzyme activates isoniazid and turns it into something incredibly toxic that would kill us.
however, it is only located in the microbacterium, thus not affecting us

Question 16

what if we we are not targeting bacteria but instead something more complex like kinases? how can we separate the drug from the poison here?

Answer 16

• there are more than 500 kinases and they all bind to ATP
• but all of the kinases have slightly different binding sites meaning selectivity could be possible if cleverly engineered
• some engineering could go as little as small changes to the non-selective molecule to make it selective (like an addition of a functional group)
• from non-selective to selective you are transitioning from a poison to a drug

Question 17

why do we need lots of knowledge of our target to separate the drug from the poison

Answer 17

• if we get a crystal image of our target we can identlify where we can extend our drug to increase potency and selectivity
• but not crucial as most common GCPR drugs we got snapshots of it a couple years ago and managed just fine

Question 18

why is desperation sometimes needed when separating drug from poison

Answer 18

Many anti-cancer drugs have pM (picomolar) potency and almost no selectivity (tumour cells are slightly more susceptible than healthy cells)
- this means the drug is toxic to your body and cancer, but we hope its more toxic to the tumour so we can recover after much pain
- if not we may die

Question 19

how do we check if the drug we created hits our target and absolutely nothing else?

Answer 19

• Selectivity screening
• Outsource broad screen against a wide range of targets e.g. kinases,
  GPCRs, ion channel receptors, enzymes, transporters – everything
  you don’t want to hit
• If the drug does hit a target then same process as for potency is
  conducted…only in reverse: aiming to make drug less potent against the unwanted target.

Question 20

how selective does a drug need to be? use an example between the unwanted target and the therapeutic target
what seperated the drug from the poison (sometimes) great potency

UNDERSTAND

Answer 20

depends on what other targets it hits and how well it binds to our target of interest
for instance if a drug is 2 nM potency on the therapeutic target but 500 nM potency on the unwanted target you have a >200-fold selectivity which is good enough for the drug to work in favour of therapeutics

if you have a 75 nM potency on our therapeutic target and the same 500 nM potency on the unwanted target, you don’t have enough of a window between the targets (<100-fold selectivity) for the drug to work on only the therapeutic target

Question 21

what is the function of the liver and what does it do to compounds

Answer 21

function:
* The liver serves to protect us from toxic substances. It
(usually) detoxifies by metabolising them into water soluble compounds which can be excreted via the kidneys.
* The liver contains enzymes called cytochrome P450s (CYP450s) which often oxidise drugs into an inactive
analogue
* This cytochrome adds a group onto the compound where a large water soluble molecule can now connect to it – this allows for excretion in the urine

Compound –> liver –> addition of polar group by CYP450s –> attraction of water soluble group –> kidneys –> secrete compound via urine

Question 22

what does the addition of a water soluble group do to the intermediate compound (metabolite)

how is the liver a problem when designing a drug?

Answer 22

the metabolite can have:
* Equivalent potency
* Reduced potency
* No activity
* Toxicity
* Different activity (MS drug metabolite may instead cause or cure cancer)
to the parent compound.

We’ve done all that work to sort out potency, permeability, solubility and selectivity…and the liver simply chews it up and spits it out. Need to find a way to protect our drugs against these enzymes…without wrecking hard-won potency, solubility, permeability etc

• we want drugs to last for 8hrs minimum in the body (no more than 3 doses of drug or else not feasible)
• often prevent rapid metabolism by adding fluorine groups and changing connectivity

Question 23

what separates the drug from the poison? Using it only as directed. explain with the example of tylenol

Answer 23

• Drug = non-toxic
• Normal metabolite = inactive and non-toxic
• Take too much and the normal metabolic route is
  overwhelmed
• Alternative metabolite is hepatotoxic and leads to permanent liver damage in case of overdose

Question 24

what does bioavailability mean

Answer 24

how much of the drug that we took initially is floating around in the body for use should be >50%

Question 25

what do we want when we take a drug in terms of a therapeutic window

Answer 25

we want a large therapeutic window between when we take a drug and get the therapeutic response vs the toxic response

Question 26

when can you call your bioactive compound a drug

Answer 26

you can only call it a drug when it actually reaches clinical trials and receives a positive response from patients. or when its on the market. before then its just a bioactive molecule