Medicinal Chemistry: The Basis of Drug Discovery

This week the learning was about identifying which hits should be promoted to lead status. It talked about different methods to pick through your hits. this was a pretty boring set of videos, as it just talked about basic reasons to remove a hit. One interesting point was the patent system, in that sometimes a discovered drug is too similar to another already patented drug, so a chemist will slightly change it to make it more patent-able. My only question is about how much these methods weed out molecules. How many compounds will chemists eventually have to test.

Once you test many compounds from your drug library and come up with your hits, you must narrow down these hundreds or thousands of molecules to leads. Leads are the compounds that are typically patented and are worked on to become drugs. The way hit are weeded out are through many methods. Firstly, many experienced chemists can visually notice by the structure of the hit will work well. They can see PAINS which means a molecule that doesn't bind to the binding site but to proteins overall, and that doesn't help to inhibit the protein. Another reason to get rid of a hit is if it is too similar to something already patented. Sometimes, a chemist will add things to change the structure slightly and make the molecule patentable. If a compound has a functional group that is known to be toxic, it cant become a drug and so there is no reason to. There are many other reasons such as metabolism and specific enzymes that will effect the viability of a hit. The path from the desire to ...

Week 12 notes Video 1 filtering hits 1 -ways to filter out hits -one way is just by looking at the compound -experienced chemists know what kind of molecules will and will not make it through certain hurdles -a recent one is PAINS -stands for pan assay interference compounds -these are molecules in the library that tend to show up on many target proteins -want to remove pains, as they don’t bind to the site, but the protein in general -very common problem -one can spot functional groups that are toxic and also can be picked out Video 2 -a set of rules called lipinskis rules -they are observed in oral drugs -molecular weight tends to be less or equal 500 -apply to drugs, not hits -Teague rules -about hits -hits should be lead like, not drug like -use lead to grow into drugs Video 3 -also should look at how the molecule is metabolized -look at which enzymes oxidize your hit -some people have different enzymes and may need different dosing -also look at metabolism ...

The learning this week was pretty interesting in giving more insight in how exactly chemists come up with the molecules that could become hits and perhaps become drugs. Also learning about the different methods of discovering drugs such as the fragment method. I was also interested in how the professor used battleship as a metaphor for searching for a drug in all of drug space. A question this week is about exactly how to search for drugs. how do they start? The professor referred to an example where a merger between two companies that specialize in different things. Where does the specialization happen? 

When discovering drugs, a large drug corporation will have a library of molecules to test against the target protein. These drug libraries are huge, with millions of molecules.The initial test are exclusively to find the molecules that best bind to the protein. This can be anywhere from 0.1%-10% of the drugs tested. then these "hits" are tested for toxicity, patents, and many other things before they can be patented themselves. Most drugs are about 20-25 non hydrogen atoms. That is a lot of combinations and to effectively search through all those atoms requires a large drug company. The newer drug companies and universities don't have the huge libraries to search through. they use the fragment method. This method requires a much smaller library, as the goal is to find two molecules that have a somewhat high activity constant, and fit into the binding sites on the target protein. these two molecules are then fused together to make a proper sized drug. The drug libraries ...

Week 11 notes -libraries allow us to sample drug space with meolecular collections -high throughput screening is our method of quickly testing our molecules -the drug space is a vast amount of molecules that could be a potentially drug -a hit had a Ki or a binding activity of binding to the target protein of around 1 micromolar -once you discover a hit through a htps (high throughout screening) go back and check if it’s pure and not decomposed -number of hits can be about .1% of the library to 10% of the library -hits can be selected by Ki value or if you have a molecule you want to outperform -when looking at a bell curve, the .1% is three std dev from mean -a library is massive, so even with .1% you have a lot of compounds to search through -you don’t want to pick the best ones, as some may not show desirable pharmacokinetic properties Video 2 - Fragment based drug discovery -the amount of molecules in the drug space is 10^63 molecules -most hits have 20-25 non hydrogen ...