Review, Refine, Redesign

Drug Discovery: Part III

Review, Refine, RedesignSo, this post follows on the story of how new drugs are discovered and developed.  Back in Kill “Bill” !!!, I explained how epidemiological techniques are used to try and identify new targets for Drug Development.  And then, in Blocks & Locks…, I described how compound libraries & natural products are used to try and find chemical agents that will bind to the target.  Now, in this post, I’m going to talk about what happens next.

…But why SHOULD there be a next step at all?  I mean, we’ve found a chemical agent that hits the target, right?  Job done, surely?

Um…no.  Sorry.  It aint that simple, I’m afraid.  In fact, the REAL work has only just started.

There are several issues that need to be fixed before your chemical agent (called the Initial Hit in the vernacular) can be turned into a drug that can progress to clinical trials.  The first issue has to do with the way that cells are put together.  The inside of every cell is full of stuff.  There are factories, powers stations, structural supports, transport systems, waste management systems… Just LOADS of stuff.  And all of it relies on proteins.  There are hundreds and hundreds of different types of proteins inside your cells, bumping into each other, reacting with each other, getting involved in cascades where one protein reacts with another & makes it go & react with a third, which goes & reacts with a fourth, which reacts with a fifth…..and so on and so on.

Now, the point is, the target you want to hit with your new drug – the “Bill” from the last couple of posts – it is just one of these proteins.  So you want your drug to hit the “Bill”.  And ONLY the “Bill”, because the “Bill” is specific to (or at least more commonly found in) cancer cells.

But!  The problem is that many of the proteins found in your cells look very similar. They have “common motifs”, as we say.  Back in Blocks & Locks…, I described the “Bill” as being like a lock, and the Initial Hit as being like a key for that lock.  So, when I say that the proteins have common motifs, what I mean is that the “locks” on the proteins all look so similar, that you need to find a very, very specific key – one that only fits the lock on your “Bill” and no other.

But, you might find that while the Initial Hit you’ve found – the one you hope to turn into a new drug – fits the “Bill” lock, it also fits the locks of other proteins too.  A lot of other proteins.  Potentially, it could fit HUNDREDS of other proteins.  And this is baaaaaaad.  The less specific your Initial Hit is, the more off-target effects you’ll get.  And if those off-target effects damage normal cells as well as cancer cells, not only will it be less effective against the cancer, it could cause very, VERY nasty side effects if you give it to patients.

The second main issue you have to consider is how sensitive your Initial Hit is.  Or, to put it another way, how much of it you need to give to show an effect.  What you need in a drug, is not just a chemical agent that hits the target, but one that shows its effects at very low concentrations, so that the amount that you need to give the patient isn’t too big.  There’s no point having a drug that hits the target perfectly, with no off-target effects, if you have to give it in a pill the size of a grand-size pizza.  Or an injection the size of a barrel.

The third main issue is the easiest to understand:  does it dissolve in water?  Lots of medical treatments are given through a drip, so your drug has to be soluble.  If it isn’t, then this is a MAJOR drawback for its clinical use.  In order to get to the tumour and have an effect, drugs have to travel through the bloodstream, so the most effect way is to put it in a drip, so it can be injected straight into a vein.  A drug that is delivered in pill form has to be digested.  Not only could the digestive enzymes affect the drug, making it ineffective, but there’s no guarantee that the drug will pass through the digestive system into the bloodstream at all, so it may not get anywhere near the tumour anyway.

So that’s your three main issues:

Specificity – Does your agent hit any other targets?

Sensitivity – What’s the lowest amount you need to show the desired effect?

Solubility – Can you put it into a solution, so it can be delivered through the bloodstream?

Now, chances are while your Initial Hit targets your “Bill”, unless you’re very VERY lucky, it’s likely to have low Specificity, low Sensitivity and low Solubility. So, your Initial Hit will have lots of off-target effects and you’d need bucket loads of it to have an effect.  Neither of which matters, as it isn’t soluble in water, so you’ll never be able to deliver it anyway.

So, this is where Medicinal Chemistry comes in.  This is the branch of science which aims to overcome these problems.  The chemists know the chemical structure of the Initial Hit.  So, they start to alter it by changing the chemical building blocks (see Blocks & Locks… again) – adding bits here, removing bits there – changing the structure, to try and improve its performance.  The aim is to increase the Specificity so that off-target effects are minimised, increase the Sensitivity so that lower doses produce maximum effects, and increase the Solubility, so that it can be delivered effectively.

This known in the trade as “Hit to Lead optimisation”.  Basically, this is where you try to turn your Initial Hit into a “Lead Compound”, ie. one which “leads the way”, and so has improved performance and is more drug-like.  Often, it is a balancing act.  Altering one bit of the chemistry might increase the Specificity, but changing that bit also decreases the Sensitivity.  Or, you might make a change that increases the Sensitivity, but the off-target effects increase.  And reduces the Solubility.

This, basically, is what a large amount of Drug Discovery research comprises of.  The medicinal chemists take an Initial Hit and tweak the structure, then the biologists test it, to see if the change has improved it.  If it has, then the chemists take this new structure and tweak it again, to try and improve it further.  Maybe it will, maybe it won’t.  So, the biologists test this new version and give the results back to the chemists, who tweak the structure again to make another version…which the biologists test….which leads to another version…which the biologists test….etc, etc, etc.

This can go on for a loooong time, as the chemists try to improve the performance of each generation of compound.  But slowly – very slowly – subsequent iterations of the chemical will (hopefully!) show improvements until a Lead Compound is developed that can enter preclinical trials.

But that’s another story….

 

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Hughes, J., Rees, S., Kalindjian, S., & Philpott, K. (2011). Principles of early drug discovery British Journal of Pharmacology, 162 (6), 1239-1249 DOI: 10.1111/j.1476-5381.2010.01127.x

ResearchBlogging.org

AG McCluskey (2016). Review, Refine, Redesign Zongo’s Cancer Diaries

You Scratch My Back…

You scratch my backThere’s a stereotype that you often see in the movies or on TV.  The lone scientist working away in isolation on his (or her, but usually his) mad scheme.  Often they will be in an isolated location – maybe on an island, or even in a castle (looks dramatic, but the heating bills are horrendous) and usually with only one assistant (who might have some peculiar trait – maybe a deformity, maybe a questionable grip on sanity).

Now, obviously, Frankenstein is the most well known of this particular stereotype, but the same tropes pop up over and over in the media.  And you won’t be surprised to learn that it’s all bollocks.

For a start, scientists couldn’t conduct their work in the middle of nowhere.  Who would fund them?  (“You want this Research Council to fund your Foul, Unspeakable Study?  Yes that seems fine….But where will you do it?  On an island in the middle of the Atlantic?  Oh, I don’t think so – that’s outside our funding area.  We have some very nice facilities at a University near you, if that suits.  No?  Oh well”)

And how would they get the equipment?  You use a lot of consumable (plastic tubes, bags, disposable pipettes etc.)  How would they get them delivered? (“What’s the delivery address?  Oh, the “Secret Bunker” in the middle of the Sahara?  I think we may need to add an extra charge on that, Sir.”)

So, like I say:  Bollocks.

Also, another thing this stereotype gets wrong is the idea that scientists work in isolation.  Quite simply, that would never work.  Science is a communal thing.  Where do most scientists work?  Universities. And universities are communal and collegiate – they are about people working together collaboratively.

Collaboration is at the heart of the sciences, certainly the biological sciences.  Look at any research paper and you will (usually) see a long list of names, and more often than not, many of the authors will be based very far away geographically.

The reason for this is quite simple.  Over time, as the generations have passed, researchers have found that their work has become focused into ever more narrow areas of interest, so that an individual researcher may be an expert in one area, but be less knowledgeable about other areas – areas which, to an outsider, may seem to be very closely related.  So, I might have a lot of knowledge about certain biological pathways, eg. DNA damage responses, but that doesn’t mean I’m an expert in DNA replication (I might know the generalities, but not the specifics).

So, in the same way, when conducting a study, it’s quite common to find your work starting to move into another area – one which you might not know that much about.  Or, you might need access to some specialised equipment that is only found in a few places in the country.   And so, you will need to work with other researchers.  Now, these other researchers are not going to do this out of the goodness of their hearts, so there has do be something in it for them.  It could be that you can help them in their work, just as they are helping you with yours.  It could be that when you combine your separate sets of data together, it opens up new avenues of research (and therefore, potentially, new sources of funding).  And this is how scientific collaborations are formed.

This is why conferences are so useful.  You might go along to a conference in your area of research, but when you are there you will meet many other people, who may be working in a similar area, or they may be in your area, but coming from an angle you’ve never thought of.  Or, indeed, they might be in a totally unrelated area, but something they say makes a little lightbulb go “DING!” in the back of your head.

Either way, you’ll start to collaborate.  And that’s how science works.

 

…although, if anyone knows where I can find a deformed, psychotic minion to do my bidding, that would be great. They are waaaaay cheaper to employ than technicians…

…….

Brown, R., Deletic, A., & Wong, T. (2015). Interdisciplinarity: How to catalyse collaboration Nature, 525 (7569), 315-317 DOI: 10.1038/525315a

ResearchBlogging.org

AG McCluskey (2016). You Scratch My Back… Zongo’s Cancer Diaries