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 ...

This week was far more interesting to me due to the focus shift to chemistry. I am learning that I definitely prefer chemistry over biology. Learning about specific chemical reactions in the body and the structure of drugs was something that interests me. Learning about new drugs and learning their effects on the body is also incredibly interesting. I also enjoyed this week and learning about how drugs are metabolized and how they exit the body. My question this week is about an example that was shown in one of the videos. It showed Codeine being metabolized to morphine. does the codeine cause the effect or does the metabolite morphine cause it?

When someone refers to metabolism in medicinal chemistry terms, they are not referring to the number of calories burned at rest, or the use and replacement of organic material in the body. The are referring to the methods of how a drug is removed from the body. When a drug is taken by someone, it enters the bloodstream and is transported to other part of the body. Then, the body want to get rid of it, as its a foreign substance the body doesn't recognize. It does so by one or more chemical reactions to make it less possible to mix in with the plasma and then easier to filter by the kidneys.  How the drug is metabolized and what the body changes the initial substance to is very important for the safety of drugs. If the drug metabolizes to something extremely dangerous and toxic, and doesn't  metabolized again to something else that drug cant be given. this just another thing that must be considered and another challenge that must be overcome.

Week 10 video 1 -phase 1 metabolic reactions specifically oxidation -sp3 hybridized carbons includes dealkylation and alcohol oxidation -sp2 hybridized carbón mostly alkenes and aromatic rings in videos mostly aromatic rings -heteroatoms (non carbon) -starting in nitrogen dealkylation oxidation -visualized as a removal of a carbon group from a nitrogen atom -used with small alkyl groups, and carry prefix nor- -same can happen on oxygen atoms, the carbon Group is removed -involves small alkyl groups and uses prefix desmethyl -alcohol oxidation is very common -primary alcohols oxidize to a carboxylic acid -secondary alcohols to a ketone -sp2 hybridization ex benzene -when nitrogen are oxidized form a n-oxide -sulfur also is very easily oxidized -forms sulfoxide which can turn to sulfones Video 2 -phase 1 covers oxidation, reduction, and hydroleses -reductions are the opposite of oxidations -ketones/aldehydes to alcohols -the ketone of warfarin is reduced to provide ...

My reaction to the learning was interest. I realized that the majority of this class has been math, which I find boring. However, learning about metabolism was very interesting. The topics i find interesting is the real chemistry and biology, not so much the math and graphs. I also learn the things that I want to learn better. The part about the graphs and the concentration limits was somewhat interesting, and the equations and calculations part was pretty boring. My question for this week is about overdosing. When someone overdoses, what is happening in their body? why does that much of a substance make your body stop functioning?

When creating a drug that will be administered orally, the window between the minimum required for a proper effect and the maximum to avoid adverse effects must be considered. When this drug is swallowed, the concentration in the plasma rises, then as metabolism begins to take effect, it decreases again. This continues for each time the drug is taken, slowly adding up until the max begins to plateau. The goal is to always be above the minimum efficacy and below the maximum amount to not feel adverse effects. Another consideration is to the half-life of the drug. The goal for the half-life is 8 hours, and changes can be made to the molecule to effect the half-life. When talking about metabolism, most people think about calories. When talking about drugs, however, it has to do with the process of getting the drug out of the body. This can be done through two phases. In phase one, the single molecule undergoes a chemical change that makes it easier for the kidneys to filter the blood. In ...

Video 1 -a challenge of oral drugs is maintaining a constant concentration in the body of drug -keep the conc. above the minimum effected dose -and below max tolerated dose -these windows make the therapeutic window -the graph is a repetition based on when you take your doses -when taking oral doses, the concentration ocellates, but should never go about the max tolerated dose or below the effective dose -make changes to dosing by frequency or by size of dose -this can make it less convenient for the patient Video 2 -an exciting lecture -clearance=.693/t0.5*volume of distribution -clearance is mL/min/Kg -vd is L/kg -half-life is the x in the y=mx+b -8 hour half life is the goal -to get the ideal half life of 8, you can change the Vd and CL -lipophilic drugs tend to want to leave bloodstream more and boosts Vd Video 3 -metabolism is actually two different ideas -one is chatabolism -the other is anabolism -when talking about metabolism on drugs, drugs are not bro...

My reaction to this new learning was some interest but more impressed as to the complexity of every single aspect of a drug, and how its modeled. Every possible thing that can be thought up must be considered, as you are dealing with human lives. The models made for how the drug moves throughout the plasma are very strange, yet important for dosing. considering dosing is one of the most important parts of medicine. Making sure you give enough active ingredient where it goes into the tissues and effects the proteins is important so it works, yet you also don't want to overdose. My question is about the elimination phase. does medicine get used up, or is the only way it leaves your body through metabolism or as waste?

There are two main models when trying to interpret data based on concentration of drug in the bloods plasma. Firstly, the one compartment model. This model treats the whole body as one compartment. the central compartment is some volume of plasma, depending on weight. then when the drug is injected in, the concentration is at max, and then as the body begins to remove the medicine through the kidneys or as waste or through general metabolism. The other model is the two compartment model. This has the circulatory system as the central compartment, and the rest of the places the drug could go in a body as the peripheral compartment. This includes muscles or tissues where the drug does what its supposed to. The different ways to model the circulatory system and concentration of drug in plasma shows the complexity of the effects of drugs on the body and how to control them. The dosage when using an IV can be changed in many ways, whether its more per minute or for longer amount of time. ...

Video 1 -volume of distribution is the amount of of plasma needed to contain the drug in the body -elimination constant determines half life -one compartment model is when using an IV bolus the drug resides in the central compartment  -central compartment defines some volume -initial concentration of plasma is a hypothetical number -Do is patient dose -with this, one wants to find the volume of plasma and a mass of the drug to find concentration  -volume using the equation Vd=do/cpo  -this is how to find size of central compartment -vol is more then 2.7L, bc 2.7 L is the amount of plasma a 70kg patient has -vol of distribution is a hypothetical number -it must be more so that the drug isn’t just in the bloodstream it’s going to the tissue  Video 2 -two compartment model -IV bolus puts drug into central compartment  -drug can leave the central comparment and go to a different compartment called the peripheral compartment -the ...

This week the videos were about clearance and pharmacokinetics which was pretty interesting. i think I'm realizing that I prefer biology that doesn't focus specifically on the molecules but is more anatomy based. This week was a lot more interesting to me as it focused on chemistry and blood and kidneys. My question this week is how long do drugs last in the body? What factors contribute to that rate? and is that why when taking medicine do you have different pills per day and time in between them?

An important part of how a medicine effects a patient is how long it lasts in the bloodstream. The study of the concentration of medicine in the plasma of the blood over time is called pharmakokinetics. This involves the kidneys filtering out the blood, similar to a public swimming pool. the kidneys take some of the blood, filtering out the impurities (like the drug) and then putting the clean blood back into the bloodstream. The rate that this can be done is modeled as an exponential decay graph. With any graph showing exponential decay, there is a half life that depends on the initial concentration of the drug, and the rate at which the kidneys can work. this rate is called clearance. Clearance is important to medical researchers because of dosing, as well as the efficacy of the drug. when learning about the molecule that has promise, you should be thorough and look at every single part of the drug. This includes how long it stays in the bloodstream and how it is removed.

 Video 1 -pharmacokinetics is study of relationship of plasma concentration over time -ties into ADME from last week -Plasma concentration is mass/vol -IV bolus is is a drug that is directly injected into the bloodstream of a patient. -as the drug is distributed through the body, the concentration goes down at a curve of exponential decay -Cp 0 is a hypothetical number, because the blood will already begin to be distributed before the blood has completely circulated the body -equation of graph is usually shown as Cp=(Cp0)(e^(-kel)(t) -ideal relationship for graph -kel is elimination rate constant -units of 1/time -slope depends on concentration of drug itself -elimination rate constant determines the half life of the drug -half-life is (ln2)/(kel) -to get it linear, it can be shown as ln(Cp)=-kel•t+ln(Cp0) -kel=CL/Vd -CL is clearance, which is volume of blood that contains a drug that is cleared per unit of time -Vd is apparent volume of distribution -Vd is a vo...

With every chapter it seems that there are more and more things that play into whether a drug will be safe and effective. Whether its which molecule or how the body will respond or if your targets is important to the disease. I am becoming more and more impressed with researchers and how they are able to create successful drugs and I also am gaining respect for these researchers. My question is about the methods that they test blood. Is this done in the first stage of clinical trials? or can it be done with blood taken out of the body?

An important part of medicine and targeting the desired protein is how the drug gets from outside the body to the specific site. This can be done in many ways, mainly orally or through an I.V. Either way, the drug must pass through the blood. "Whole blood" is regular blood that is made by the body. This contains 45% by volume red blood cells, 1% white blood cells and platelets, and 54% plasma. Plasma contains mostly water, with some proteins and hormones the body produces. when designing a molecule, one must consider how the molecules in the blood could alter the drug. another thing to consider is how the drug will do when the kidneys try to filter it out of the blood, or how the liver will try to destroy it if it enters the body orally. There are countless amounts of things one must consider when making a drug, at every step there are many things that can effect how your drug and make it ineffective or even toxic. even if you have a promising molecule, it may not respond w...