Drug Discovery, Part II
So, in my last post, I spoke about the early stages of Drug Discovery and described how Epidemiology is used to identify promising targets for drug intervention. In this post, I’m going to describe some aspects of the next stage in the process, namely how we try to identify chemicals that hit these targets and then develop the chemicals into active drugs.
The world is full of chemicals. The world is MADE of chemicals. YOU are made of chemicals! Just think about that. Everything you are, everything you see is made up of a mind-boggling number of chemical molecules, which are made from a relatively small number of ingredients. Most of it is made of carbon stuck to some oxygen, some hydrogen, a bit of nitrogen, and a tiny amount of other elements like sulphur, copper, iron, chlorine…..etc.
But the point is, this small number of ingredients can be stuck together in an almost infinite number of ways. Think of it like Lego, with each element represented by a differently shaped piece. You don’t need that many different shapes, but you can build anything you like.
Now, the point is, having used the Epidemiological studies I described in Kill “Bill” to identify a promising target for drug intervention, the next step is to try and find a specific chemical structure that will stick to the “Bill” and stop it working.
Basically, think of the “Bill” as being like a lock. What you need to do, is find a key for that lock – one that fits that lock alone. So what you need is a chemical structure, built from the chemical Lego of carbon, hydrogen, oxygen etc, which acts like a key and will slot exactly into the lock.
There are several ways to do this. One way to find your potential drug is to design a chemical structure that will bind to your target exactly. So, if you know the shape and structure of your lock, you can use the chemical Lego to try and build a key from scratch.
Also, you can look at Mother Nature. Nature is great. There’s loads of stuff there. Moulds, bacteria, yeasts, mosses, fungi, flowers, berries – seriously, loads of it. The natural world is packed with a dizzying myriad of different species, which have evolved to survive in a huge range of environments. And, to do this, different species make molecules which they can use to promote their own survival, molecules which are built up from the chemical Lego. Now the thing is, some of these constructions have benefit to us, ie. they have medicinal uses. This aint news – it’s how medicines have been discovered historically. But, as well as this, because there are so, so many of these natural products out there, it’s also possible that some of them may also act like a naturally occurring key for your “Bill” lock.
Now, whichever way you go, the important bit is to a) find your key and b) make sure that your key fits the lock. And one of the great things about the modern world is that modern computer power makes this process a lot easier. Across the world, there are huge databases of chemical structures. Some of them are from natural products, some of them have been made synthetically. Now, if you know the structure of your lock, you can search the databases for chemical structures that are likely to bind – ie. search for keys that fit the lock.
Alternatively, maybe you have a chemical compound and you want to know how it works. In that case, you would look for complex protein structures it might bind to – ie. you already have a key and you search for the lock that it might fit.
Now, whichever way you approach it, you will end up with a key and a lock. But that aint the end of the process, oh no…..that’s just the start. Because after all, does the key you’ve found fit only that lock, or does it fit hundreds of other locks too? How can you tell?
Well, that’s another story……
Harvey, A., Edrada-Ebel, R., & Quinn, R. (2015). The re-emergence of natural products for drug discovery in the genomics era Nature Reviews Drug Discovery, 14 (2), 111-129 DOI: 10.1038/nrd4510
AG McCluskey (2016). Blocks & Locks… Zongo’s Cancer Diaries