Drug Discovery and Weight Loss with Webster Santos

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Travis

Do you know the process for developing a molecule into a drug that you and I could benefit from? Well, I don't. That's no surprise, right? But thankfully, Virginia Tech's Webster Santos is an expert in this very topic and was kind enough to join me on the podcast to explain this process as well as a chemical compound he's working to develop that he believes could help folks lose weight without exercise and while retaining muscle.

Webster is a professor of chemistry and the Cliff and Agnes Lilly Faculty Fellow in the College of Science. He also directs the Virginia Tech Center for Drug Discovery, which is affiliated with the Frail and Life Sciences Institute. Webster broke down the rigorous and lengthy process of drug discovery. He also explained what some of the challenges are there and why interdisciplinary work is really a key to unlocking some of the potential of these compounds. He also shared insights on the chemical compound he's working on related to weight loss,

He explained what it's doing on the cellular level and how that's different from some of the other weight loss medications you may see advertised for on television. Be sure to like, rate, follow, and or subscribe to the podcast. I'm Travis Williams and this is Virginia Tech's Curious Conversations.

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Travis

But was thinking maybe a good place to start this conversation might be to simply talk about the Center for Drug Discovery and what that process is. So what is the process for, I guess, discovering a drug?

Webster

Yeah, that is a very complicated process. Drug discovery really starts with the identification of a target along with a molecule that might inhibit that target. What we are interested in is a small molecule that would bind that target and alter its activity. So typically that's associated with a disease. And so taking that small molecule from inception that is identifying the first hit compound. The hit compound is something you start with and you could tinker with. So basically we modify that molecule, add different groups to it to see if it gets any better in terms of activity. Once it has a profile that is interesting and good for us, then we then start the process of discovery, which is modifying the molecule so that it becomes what we call drug-like. In other words, it is suitable for eventually for human consumption. So yeah, guess that we're trying to do here is just to develop those molecules really.

Travis

Yeah, and so when you are starting to find or identify a drug, you... How does that work? Do you start most... Do you start often from finding a molecule or a compound that's acting a certain way or do you start with a problem where you're looking for a compound to do something? guess, like which end of the spectrum do you start from or maybe is it sometimes both?

Webster

Yeah, you could do all of it. So we have done all of those. So there are cases where we're like, OK, there is a small molecule that binds a receptor or a target protein. And we know what the substrate looks like. And so we could say, hey, we could take that substrate and make changes to it so it becomes an inhibitor. And there are cases where we would say, OK, there is no starting point we need to figure out a good starting point for a small molecule inhibitor. In that particular case, we would screen a library. For example, from the Virginia Tech Center for Drug Discovery screening library, we would screen 40,000 compounds in the hope that we will find one molecule that could be a basis for our starting point in terms of the inhibitor development.

And so we have done all of those and we've been lucky enough to be successful in both that.

Travis

How many people roughly are a part of the Center for Drug Discovery?

Webster

So there's about 60 people. They are coming from different colleges throughout the university, from chemistry to engineering to Freeland Biomedical Institute, all the way up to Arlington, Children's Center.

Travis

Yep. what is the benefit of having kind of a multidisciplinary approach to finding new drugs?

Webster

This is a key question here, right? So, you know, we need all possible expertise to be successful in taking a small molecule or like one target and one compound into fruition in terms of translational effect. And so that means we need chemists. Chemists would make molecules and modify the molecules. We will need pharmacologists to figure out, you know, what these molecules do and the whole animal we would need clinicians because we typically have a patient population that we want to affect. We need structural biologists to figure out how these molecules work in terms of their atomistic interactions. And so we need everybody's expertise to kind of put all of this together. And so the more expertise we have around a problem, the more successful we are.

Webster

Yeah, well, I know I want to get to talking to you about a recent drug discovery that you're working towards, but I am a little bit curious about this process. What's the process of taking something from a compound all the way to something that I can use? What are the stages in between there? is there a turning point in there where you get super excited, like a breakthrough moment?

Webster

Yeah, no, absolutely. If you may, there are many breakthrough moments, right? And so the first one might be like, OK, we have a hit compound, which means we have a starting point molecule, because it might have taken three years to find that one molecule, right? And then developing that molecule into more of a drug-like compound that is something that we could start to put into animals, we would call that another eureka moment, like, ha, we've had something.

And then we might have to optimize that molecule so that we could now dose that orally in an animal like a mouse or a rat for once a day dosing. Because as you might be wondering, the best way to administer a compound to a person is by oral administration. That's easier than an injection, for example or things like that. I for certain types of diseases, this is most optimal. And of course, once a day dosing is best because people will comply with once a day dosing three times a day. That's going to be very tough. So any oddball type of regimen people won't really like. And so this process is actually very lengthy, right? So this takes about $2 billion per compound to make it from an inception to a drug is about $2 billion. And that is about, on average, 12 years to develop a drug from inception to FDA approval.

Travis

Yeah, I don't think most people realize how long it takes.

Webster

Yeah, and so actually just to process that a little bit more, right? So we might have a starting point compound that we could put in animals that has efficacy in animals. give that to a person, there's a long list of toxicology, toxicity studies that we have to go through and clear before you can even dose that into a human. So you would need two toxic species, for example, a rat and a dog or a rat and a monkey depending on what indication is, maybe 30-day chronic dosing is required. And if you clear all of that, you could file an IND status at the FDA. If that's get approved, you could give it to humans. So it would then go to phase one clinical trial. And so there are three phases of clinical trials, so phase one, two, and three. The early stage, which is phase one, is so-called the first in-human trial where you're actually giving the molecule to a person without the disease, really you're looking at, know, is it going to be safe? Is going to have side effects? And so you start dosing a low dose, looking for any bad effects. And then you slowly, incrementally increase the dose. If that gets cleared, then you could undergo a phase two clinical trial where you now do a study in the patient population, but it is significantly smaller you're really looking for a signal that, this therapy might work in this specific indication. And if you're ever so lucky to make it through that, you could do a phase three clinical trials where you could take a big cohort, big population that has the disease, you treat them, and you ask the question, did they statistically help the patient population? And if that all works out, then you submit it a new drug application to the FDA. Then cross your fingers.

Travis

I was gonna say, sounds like a very rigorous process. Absolutely. What's the percentage of things that go through that whole process and it works out correctly?

Webster

Very, very low. Very, very low. Somewhere around like 2 % of molecules pass it through. anywhere from, depending on the year, two to 10 compounds get approved by the FDA per year.

 

Travis

So we're not even talking like batting averages at this point. We're talking like the average is maybe like a hole in one on a golf course or something.

Webster

Exactly, exactly. There's a lot of, you know, there's a lot of guessing game and actually more importantly luck.

Travis

Well, I know you recently got, you were one of 10, I think, proposals selected for proof of concept grant through launch here at Virginia Tech, and that was for a chemical compound to enable weight loss. And so what stage in that process is that compound and what do you hope that that's going to do?

 

Yeah, so yeah, that's actually a very exciting project. And if I could sum it up in a slogan, if you may, would be like, we're putting exercise in the pill. And so we're trying to enable people to lose weight without doing any exercise. And we do that by increasing metabolism and by going through the mitochondria. That's not exciting. And so for folks who are not aware of what the mitochondria is, it is an organelle in the cell that makes ATP. ATP is a molecule that allows you to move, right? So it's kind of like the energy currency of the cell. And so basically we're saying, you know, with our molecules, we're making the mitochondria work a bit more. In other words, if the ATP costs $1, using our small molecule is now $1.25. Right, costs a bit more, that is it costs a bit more energy to make it. And so we've been working in this field for a bit of time, over 10 years now. And we've developed small molecules that are drug-like, that we have put in animal models of disease. In this particular case, we put this in diet-induced obesity models in animals. So this is in mice. So you could...induce weight gain in animals by giving them fatty food, if you may. And then we ask the question, will these animals lose weight when we give them our compound? And so we've shown, and we published many of these, that the animals lose weight with our compound. And so this is a proof of concept grant. And so what we do then is to try to take these basic ideas from the lab into the clinic through translational work.

And that would mean we now begin to remove the work from my lab and really asking the question, are these compounds safe to use in mice and in higher odor species? So we're in the early stages of this. We're hoping to be doing some sort of I &D enabling studies in the future.

Travis

Correct me if I'm wrong, but you did it with, you've done a study with one animal and now are you moving to the two animal study with us? Is that what the next step is?

Webster

Yeah, so actually this is quite a lengthy process. these are baby steps. So for example, you might want to look for, is this compound safe in animals over 30 days? But before you do that, there's a baby step, is dosing animals at low concentration every day. So sorry, slowly increase the concentration and looking for the maximum tolerated dose. So this is like a, we would call that dose range finding. We're trying to find out what is the safe level of drug that could be administered to an animal. And so we kind of guess, you know, not guess, but kind of figure that out. And from that, we will do a mid study where instead of 30 days, we'll do seven day study looking at, you know, what appropriate drug concentration would be useful in the 30 day study me if I'm understanding what the potential for this drug is. I could just take it and basically myself would exercise, would get a workout and would burn more calories. And so then I would theoretically lose weight.

Travis

How does that differ from some of the popular drugs that we see? I don't know about you, but I see like weight loss drugs on TV commercials all the time now. How does it differ this compound? How might it differ from some of these more popular ones?

Webster

That's a great question. So I think what you're thinking about are the Wigovite type, Ozempic type. These are traditional type 2 diabetes drugs that were found to induce weight loss in humans. So yes, these work very well. And so what these molecules do, the Ozempic type, is that they tell your brain that you're full. And then, so their appetite suppressants in that case.

And also there is a slowness of gastric emptying. So food moving through the gut, if you may, is slower, and so now you have this sense of fullness. And so in other words, what they do is they minimize energy in. So if you eat less food, of course you're going to lose weight. And they actually work very well. You could lose up to 20 % weight with these drugs.

Now, we, and those drugs, by the way, are done by injection. So they're quite expensive, they're peptides, and you have to do it by injection. We're on the opposite side of the coin, right? So I said, we're going to increase energy expenditure. So is the energy out? So anything, any energy put in, we're going to burn more, you know, per unit ATP, essentially, so that you could do the weight loss.

So we're on the other side of the coin. We are not an injection administration. We hope that we're going to be able to do this by oral dosing. So we'll just take a pill once a day over time. And hopefully, one would lose weight if it all works out.

Travis

Yeah, and it sounds like, and I'm not a doctor, so tell me if this is wrong, which is how I should, I probably should have named the podcast that. Tell me if I'm wrong about this. But I guess I'm curious if a person is continuing to eat, it seems like they would be continuing to get all the nutrients that maintain their bodies and stuff. And I'm asking about that specifically because I've heard with some of those other types of drugs that it's hard to retain muscle mass because you're just simply not eating enough food. So what do you think the potential is maybe for this compound related to that?

Webster

Yeah, so that is a very good question, right? So the ozempic type or GLP-1 agonist class of compounds, up to 40 % of the weight loss actually comes from muscle mass loss, right? And so if you're losing weight, one would hope that you're only going to lose fat mass and not muscle mass, especially for the elderly folks, right? So that, you know...There's a lot of muscle loss as one ages. And so if you lose even more muscle, then that could be very, very problematic. And so in this particular case with our compounds, the animals will eat whatever we feed them. So they get the normal nutrients from the food. So in certain studies, for example, we feed them high fat diet, kind of like a McDonald's type of food, if you may. And we still see weight loss. And in fact, the weight loss that we see is coming from fat mass and not from muscle mass or bone mass. And so to us, if it translates really well to the clinic, that could be very powerful.

Travis

I also read that having more muscle mass is one of the keys, a lot of people say, to simply your body burning more calories, you're having a higher metabolism. This is what I saw on the internet. So I don't know if that's true or not.

Webster

it's true actually, right? Because muscle, that's got a lot of mitochondria, right? And mitochondria is what produces ATP. so, yeah, so if you force your muscles to move, exercise, for example, yeah, this is where you spend a lot of energy.

Travis

Yeah. Well, I'm curious with some of the initial studies you've done, how's the energy level? Has it been impacted in the animals when their cells are burning more energy?

Webster

Yeah, you know, I don't quite know how to answer that question because we have not put this in people. So just to be clear, we have not put this

Travis

couldn't tell you if they were tired is that what you're saying?

Webster

Well, they won't, but you would know if they're sick, if there's something wrong with them, they hunch down, they stop moving if you poke them. So there are signals that they will tell you that there's something going on with them. With our compounds, mean, obviously, if you overdose them, you're going to make the animal sick. And so you're going to know their stick. But the key here is that you could dose them up to the therapeutic level. And over long periods of times, we don't see any ill thrift with the animals.

Travis

Well, that's fascinating. Well, that does sound super promising and I'm really excited for you to continue pursuing that because it sounds like there's a lot of potential specifically for like you mentioned, folks as they're getting older. I know that all the relatives that I've had as they've gotten older, have had, you you have trouble losing that muscle mass and you you need that to be able to do the fun things you want to do in life.

Webster

That's very true. And as you already know, obesity is related to many other diseases. Front and foremost would be type 2 diabetes. So if people would just lose weight, people could get off. They'd get better in terms of diabetes. So people on the Zempik, if they lose enough weight, diabetes goes away. And so we're hoping that if you could kind of help mitigate this obesity problem, the associated illnesses would also get helps cleared out.

Travis

Well, I guess one last thing that I'll ask you before we go here is, what would you most like for the average person to know about the drug discovery process?

Webster

Yes, I hope that people appreciate that it is a long, painful process. It actually, you know, there's a lot of back and forth trial and error, lots of testing, and there's a lot of controls before a compound gets out. It's been tested a lot. And before it gets approved by the FDA, rest assured that, you know, all the necessary precautions been fulfilled.

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Travis

And thanks to Webster for helping us better understand the drug discovery process as well as the compound he's working on related to weight loss. If you or someone you know would make for a great curious conversation, email me at traviskw at vt.edu. I'm Travis Williams and this has been Virginia Tech's Curious Conversations.