Post by Amtram on Feb 7, 2014 12:48:25 GMT -5
This really had to be a separate thread. Why drug discovery is hard – Part 2: Easter Island, Pit Vipers; Where do drugs come from? The article starts with pharmacognosy - the discovery of medications in nature, and understanding what element of the natural treatment is the one causing the medicinal effect. It proceeds to explain not only how we have learned to create medicines using what we know about extracting them from natural compounds, but also how we learn to create them using the techniques we developed from that.
Fascinating stuff. Go read it.
But nature, as inventive as its evolutionary processes are, cannot supply us with all the drugs we need. This is where the ingenuity of chemists comes in. The major triumph of chemistry, one which makes it unique among all sciences, is its ability to discover, design and synthesize molecules that don’t exist in nature. Chemists can either tinker with existing molecules or create new ones from scratch by arranging atoms in specific configurations, a feature that makes chemistry an art akin to architecture. The employment of chemistry in the service of medicine has been one of the most successful scientific stories in history. Over the years chemists have finely honed their capacity to rapidly make millions of compounds efficiently and in pure forms. They can test these millions of compounds and see whether any of them bind against protein targets, a feat helped to no small extent by automation and robotics. This process is called high-throughput screening (HTS), which as the name indicates can test millions of compounds against proteins or cells in short order. When it became fashionable in the 80s and 90s, HTS was regarded as something revolutionary; after all if you ended up testing tens of millions of molecules against any disease or protein, surely you would find at least dozens of promising leads. Sadly that dream has not come true, and while HTS is valuable it has turned up very few leads which were then optimized into drugs. As with natural screening, HTS success rates can also be quite low.
Why is this the case? Well, one reason is a fact mentioned in the previous post, namely that nature had very little evolutionary incentives to create proteins that would bind to synthetic drug molecules that would appear on the scene billions of years later. Another reason is that you may be testing the wrong molecules and trying to put a square peg in a round hole; in that case quantity will never trump quality. Also based on the previous post, it’s obvious that not all proteins are created equal and therefore it can be much harder to find hits for certain proteins compared to others. What is worse is that it’s often very difficult to gauge this success rate beforehand. Thus as often turns out to be the case in science, nature is a very harsh mistress, yielding her secrets with great reluctance. If you want to find a small molecule that binds to an important protein, you are going to have to work for it.
Why is this the case? Well, one reason is a fact mentioned in the previous post, namely that nature had very little evolutionary incentives to create proteins that would bind to synthetic drug molecules that would appear on the scene billions of years later. Another reason is that you may be testing the wrong molecules and trying to put a square peg in a round hole; in that case quantity will never trump quality. Also based on the previous post, it’s obvious that not all proteins are created equal and therefore it can be much harder to find hits for certain proteins compared to others. What is worse is that it’s often very difficult to gauge this success rate beforehand. Thus as often turns out to be the case in science, nature is a very harsh mistress, yielding her secrets with great reluctance. If you want to find a small molecule that binds to an important protein, you are going to have to work for it.
Fascinating stuff. Go read it.