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There's something called structure activity relationship (vaguely, because there's a lot of subdivisions), that explains/predicts how certain patterns of structures and pharmacophores bind to certain receptors and proteins. By knowing the physiology behind certain disorders, what genes, receptors, proteins and celular structures they affect, you have some theoretical targets that holds some potential for being where a drug will have it's mechanism of action interfering with.

After some ligands to some targets are known, you may use them as skeletons to serve as a base. By making some changes in specific places, for example, you'll have changes on how fast they're metabolized, how well absorbed they re through a route of administration, how potent they are and wether they are agonists (i.e. they activate the receptor), antagonist (they bind to the receptor without activating, preventing other ligands to bind and activate), inverse agonists (simplifying it, they bind and cause a "reverse" signaling). If the target is an enzyme, it could be an inhibitor or an inducer. Overall, such small changes with new ligands called radicals produces analogues of the drugs and the molecules are then studied individually to see which of them do the best job to a purpose. Often, some discoveries may happen to be accidental too, by screening the biological activity of a molecule for a purpose and later, on pre clinical studies, clinical trials or even post-market, it's found out that they are also useful for something.

It's kinda hard to simplify every possible process, especially because I mainly study the design of new psychoactive substances and that's a very specific case.

An example could be a drug used to treat high blood pressure. Take propranolol or atenolol for example. It was known that the activation of noradrenergic beta receptors increase blood pressure, then, having something that blocks it, i.e. a beta blocker, will prevent endogenous sympathetic stimulation to activate them. If you look at both molecules, you'll see the similarities. See also salbutamol molecule and compare it to adrenaline and noradrenaline. It's basically an analogue which activates beta 2 adrenergic receptors.

Edit: I feel like I've oversimplified too much. If you're interested on structure activity relationship it, you can have some fun by playing a little bit with swisstargetprediction.ch and put a molecule on it, then make a little change here and there and checking which kind of ligand do something. It's a good starting point for learning and for fun.

1. by screening tens of thousands of samples taken from anywhere and everywhere (trenches in the depths of the sea near Japan, etc.), in an automated fashion or otherwise
2. by using computational simulations (like DFT) to determine the types of molecules that demonstrate desired affinities, and synthesizing

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There are certainly a lot of educated guesses in the process, but it can't be overstated how much pure brute force is involved. There are warehouses full of robots sticking potential compounds into test tubes, one after the other. Millions of experiments per day.

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Hey there, I work in pharma, specifically in drug discovery for oncology and rare genetic diseases. Essentially, it's a very long and complicated process, and there's not just one way to do it. Every disease area has its own challenges and methodologies. I'll do my best to give a general overview.

First off, you need a target. A target is typically a protein (but not always) that you are going to try to interact with with a small molecule (what you would think of as a drug). The first step is to determine that there is a causal relationship between the target and the disease. In some cases this is easy, in some cases you can at best prove a peripheral relationship, this is usually where multi-drug therapies come in, like in oncology.

Once you have a target and you can prove via experiment that the target causes the disease, you need an assay. An assay is a test, something that a biologist can put a chemical compound into and determine if it's doing what you want to the target. Sometimes that's shutting the target down, sometimes it's activating it, sometimes that's helping it fold, and so on. Whatever activity you need, the assay tells you if it's working or not.

The next thing that you need is chemical matter. Drugs that you put in a pill are not the only drugs though, so the path is a little different for things like vaccines, antibodies, etc. If we're talking about something that you can put in a pill though, the most common way to start finding chemical matter is through something called at High Throughput Screen or a Virtual Screen. A High Throughput Screen (HTS) is where you take a purchased library of very diverse chemical matter and just test it with the assay to see if any of the compounds do what you want them to do. A Virtual Screen is dependent on whether or not you know what the target looks like and can use computers to model in 3D the target and small molecule to better make decisions about what to test with the assay.

If things work out and your HTS or VS give you a "hit", then you start working on hit expansion. You take that small molecule and make a bunch of little changes. This lets you feel out where changes are tolerated and what parts of that small molecule are essential for your activity. This can take a while. Teams routinely make thousands of what we call "analogs" of our starting hits.

Once you start routinely making very potent compounds, that is compounds that you only need a very small amount of to have the desired effects, you start optimizing for the things that make the potential drugs work well within the body. It's not enough to have a compound that engages your target well, it also has to play well with everything that makes you a human. We use a variety of cells and animal models to make sure that the compounds get transported to the parts of the body we need them to get to, that they're not metabolized in nasty ways by your liver (I'm looking at you acetaminophen), and they stay in your body long enough to have the effect that we need. This is what we refer to as "Late Stage Lead Optimization".

The last stages of this part of the process give us what is called a "Human Dose Projection", which is our estimation based on a lot of data, how much compound we need to put into a person to have the desired effect, whatever that may be.

After that, it's on to human trials. We file a LOT of paperwork with the FDA to being the trials and start recruiting for clinical trials. There are four stages of clinical trials, but the first three are the ones that really matter.

Here's the breakdown:

Phase 1: Healthy volunteers. This is how we show that the drug is safe. We dose a small number of participants with very low doses and watch very closely to make sure that we don't have any bad side effects. If it looks safe, we increase the dose towards what we think is the higher end of what we need to have our desired effect. There are exceptions for "healthy" volunteers, in the event that the risk to the patient for side effects may be outweighed by potential benefit. A good example of this is if we have a very sick cancer patient and a drug that may help them live longer or recover, even if the treatment has side effects.

Phase 2: This is the stage where we have to prove statistically that it works and what the optimal dose is. We dose a larger amount of patients, usually exclusively with the disease (instead of "healthy" volunteers) and try to determine the best dose and dosing protocol, for example, does one big pill once a day work better than two medium sized pills? We try to find the best way to treat the disease while still keeping side effects to a minimum.

Phase 3 is the big one. We dose a much larger patient population and have to prove that whatever drug we're proposing is better than the current treatment available on the market. We have to prove that it's safe, tolerated, and effective. Once the trial is completed, all the data goes to the FDA and they make the call on whether or not the drug is approved. If the drug is approved, it goes on the market, and doctors can prescribe it for the disease it's intended to treat.

Phase 4: Once the drug is on the market and available to anyone who needs it, a field called pharmacovigilance kicks in. These are the folks who look for rarer and more severe side effects that you may not have seen in a smaller trial. Any time you go on a medication, have some bad effect, and report it back to your doctor, that will get back to the drug manufacturer. We literally have teams that watch social media, conferences, literature and so on to look for these rare bad effects called "Adverse reactions". If enough of these happen, the FDA can recall a medication or give it what's called a "black box warning".

To specifically address your question about combination of chemicals, that's typically done when there's not one single target that causes the disease. For example, cancer needs a LOT of stuff to go wrong in your cells for the disease to form. In these cases you typically will pair one new drug, with other already approved drugs to try to hit multiple targets at once. It is exceedingly rare that two new drug molecules will be trialled at the same time, since there are so many variables to control for when it comes to safety, side effects and dosing.

If you have any follow up questions, I'm happy to expand on any of this.

This is the answer right here.

Edit: I feel like it's worth adding a comment about how big chemical libraries are and how big chemical space is. For the uninitiated, "chemical space" is the number of different molecular structures that can be made. For drug-like molecules, an oft-quoted number is on the order of 10^30 to 10^60 different chemical compounds. This is an astronomically large number; think "number of stars in the known universe" large. For perspective, the largest screening libraries are in the millions of compounds (10^6) and virtual screening libraries are in the billions (10^9), but they're always getting bigger. Finding new drugs is truly an undertaking.

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Woah I just had a thought. But first, is the reason they are getting bigger based on manual or computer programmed input (probs a combination of both)? Like do we have program that has a set of laws that say create this compound based on 118 elements, but if it’s this element don’t add this element, and if it’s this element and this element don’t add this many bonds etc,? Also, when you do these screenings, does a computer program run through a combination of compounds and targets and how they interact? This is so fascinating.

What's wrong with Acetaminophen? I realize I could google that but I almost understood everything you said so Imma ask you instead. (Thanks for the write up. Super fascinating)

It's extremely aggressive to even healthy livers.

Some people show signs of jaundice after a standard 2 pill dose.

It was released when trials weren't as rigorous.

It would fail today's clinical trial standards, and it's also really only an antipyretic. It doesn't kill pain for most, only lowers temperature.

Could you expand on what you wrote for phase 4 please? All of what you wrote there sounds really interesting.

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/u/Corpcasimir hit it on the head. Acetaminophen would never make it to market today. The window between "this works" and "this kills you" is so small for that drug that it's scary that you can just buy it over the counter.

Whenever you take a drug, your body has mechanisms that "see" that it's not something your body has produced and is not food/nutrition. It will then take steps to modify that compound chemically to get it out of your body. For Acetaminophen, the majority of is is metabolized to something you can just pee out. A small amount of it is converted to something else though, something reactive and extremely toxic. Get enough Acetaminophen in your body, or even if you just happen to metabolize it more in the "bad" way, and you get this stuff building up. What literally happens is that it physically reacts with the proteins that control energy production in your cells. No way to make cellular energy = cells die. Enough cells die, your organs start to fail. So yeah. Don't take acetaminophen if you have any other option.

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Damn that's crazy. Thanks for elaborating I appreciate that