5 – Overview of Drug Discovery Process (S1E5)

Hey everyone, have you ever swallowed a pill
and thought, how in the world did someone even
figure out how to make this thing? I know I have.
It really is incredible when you think about
it. Yeah, so today we're gonna do a deep dive
into this whole world of drug discovery. Sounds
good to me. Specifically we're focusing on like
those very first steps. You know, how do you
go from a scientist having like an initial aha
moment to that turning into an actual medicine
that people can take? Right. It's a long road.
Right. It is. So basically, imagine you've handed
us like a stack of research papers, a bunch of
notes. Yeah. Like how do new drugs actually get
discovered? Our mission today is to take all
that information and like boil it down to the
most important, coolest stuff. Yeah. Try to make
sense of it all. Exactly. And I think you're
the perfect person to help us do that. I'll do
my best. You eat, sleep, and breathe drug discovery.
Well, most days at least. So you're going to
break down the science for us, but also show
us how amazingly complex it is. It definitely
is. So are you ready to get started? Definitely.
Let's go. OK, great. So first off, we need to
wrap our heads around just how big of a deal
this whole thing is. I mean, we're talking 10
to 15 years. Oh, yeah. At least. And. billions,
billions of dollars to take a drug from like
a scientist bench in the lab to an actual medicine
cabinet, right? It's a massive undertaking for
sure. Massive. And, you know, our listeners have
specifically asked us to like zoom in on those
really early stages. OK, yeah, the early stages.
That initial like spark of an idea where they
find a molecule that they think might actually
work as a medicine. And how do they even know
where to start? So it all begins with something
called high throughput screening. Right. Sounds
kind of fancy, right? Yeah, it is a bit of a
mouthful. It is. But basically, it's kind of
like imagine a lab where robots are doing all
the chemistry work. OK. And they're testing thousands,
even millions of different compounds against
like a specific disease targets. You can almost
think of it like a giant chemistry lottery. Oh,
I like that. That's a good way to put it. Yeah.
OK, so that makes sense. But where do all these
compounds even come from? It's not like they
just magically appear. Yeah, not quite magic.
But it's pretty cool where they come from. You
have these huge libraries of chemicals that have
been, you know, built up over the years. Some
of them have been made in labs. Others, they
come from natural sources like plants. Oh, interesting.
And increasingly, scientists are actually using
computers to just design new molecules from scratch.
Wow. So, you know, it's really a cool mix of
like old school chemistry and like super cutting
edge tech all kind of coming together. OK. So
you've got these robots. They're sifting through
this giant library of chemicals. What are they
actually looking for in this like molecular lottery?
So they are looking for what we call a hit. A
hit. Which is basically a compound that seems
to do something to the disease target that we're
interested in. Okay. So for example, let's say
we're trying to make a new painkiller. Okay.
A hit might be a compound that blocks a certain
receptor that's involved in pain. But, and this
is important, a hit is just the first step in
a very, very long journey. So it's like finding
a diamond in the rough, right? It has potential.
but it still needs a lot of work before it becomes
like that beautiful sparkly gem. That's a great
analogy and that's where medicinal chemistry
comes into the picture. Okay, so tell me more
about that. So medicinal chemists, they are the
master crafts people who take this promising
hit compound. Okay. And they're carefully modifying
it, tweaking it to try and turn it into something
that's safe and effective as an actual medicine.
Okay, so what are some of the challenges they
run into? because it can't be as easy as it sounds,
right? Oh, no, definitely not. So, for one thing,
the het compound, it might be toxic, you know?
It could break down too quickly in the body.
It might not even get absorbed properly. Sometimes
it could even interact in a bad way with other
medicines that someone's taking. Oh, wow. So
there's a ton of obstacles that they have to
overcome. So it's kind of like a giant puzzle,
right? You're tweaking this molecule, but each
change could have some unintended consequence.
Right, exactly. It's a really delicate balancing
act. They have to boost the drug's effectiveness,
but also make sure it doesn't cause a lot of
side effects. And then also you have to make
sure that it can be made into like a pill that
someone can actually swallow or an injection
or something. Right. Practical stuff. Exactly.
It's not easy. So I'm curious, do you have any
examples from your own work at OPR &D that can
kind of bring this all to life? Like how does
this actually work in the real world? Oh yeah,
definitely. Let me tell you about this one project
we were working on. It was a potential new treatment
for Alzheimer's disease. Oh, wow. OK. And we
had found this hit compound that seemed really
promising. It showed really good activity against
one of the key enzymes that we think drives the
disease. That's amazing. So you guys had this
potential breakthrough on your hands. What happened
next? Well, unfortunately, we ran into a big
problem pretty quickly. The tests showed that
the compound was being metabolized super fast
in the liver. So it was basically getting broken
down by the body before it could even reach its
target in the brain. Oh, that's gotta be so frustrating.
It's like the compound got lost on its way to
fight the disease. Yeah, exactly. So what did
you guys do? Well, it was a setback for sure,
but it's actually pretty common in drug discovery.
So we all put on our medicinal chemistry hats
and we started brainstorming, like how can we
tweak the structure of this molecule to make
it more resistant to metabolism? Okay, how do
you even go about doing that? Do you just like
randomly start changing things until something
works? Ha, no, I wish it was that easy. It's
actually very systematic. So we used computer
modeling to try and predict how different modifications
would affect the properties of the molecule.
Oh, cool. And then based on that, we synthesized
a bunch of different versions of the compound,
each one with just like a tiny little change
to the structure. OK. And then we tested all
those in the lab. So it's like being a molecular
architect, right? Yeah. You're carefully redesigning
the building blocks of this compound. Yeah, exactly.
To get what you want. It took a lot of tries,
but finally, after a ton of rounds of designing,
making these new compounds and testing them,
we finally found one that was much more stable
in the body. That's amazing. Yeah. And the best
part was it still kept its activity against that
target enzyme that we wanted to hit. So you outmaneuvered
the liver. You outsmarted it. I guess you could
say that. It was a big win for the team, for
sure. I bet. But of course, that was just one
of many hurdles to get over. There's a ton more
challenges to tackle before this compound could
actually move on to the next steps and eventually
become a medicine. Right. But this is a really
good illustration of how important medicinal
chemistry is. You're taking this promising hit
and turning it into something that could actually
be a drug someday. Exactly. It's a challenging
field, but it's so rewarding to be a part of.
You mentioned stability. What are some of the
other things that medicinal chemists have to
think about when they're refining these HIC compounds?
So another big one is solubility. The drug, you
know, it needs to dissolve properly in the fluids
in your body so it can get absorbed and actually
reach its target. Right. Makes sense. It's like
when you dissolve sugar in water. Some things
dissolve easier than others. Exactly. And if
a drug doesn't dissolve well, then it's not going
to get absorbed very well, which means it's not
going to be as effective. So medicinal chemists,
they spend a lot of time trying to improve the
solubility of a compound. Sometimes they tweak
its structure. Other times, they explore different
what we call formulations. Formulations. What
does that mean? So that's basically how the drug
is packaged. Like, is it a pill? a capsule, a
liquid, all those things can affect how it dissolves
and gets absorbed in the body. Oh, interesting.
So it's not just about the molecule itself. It's
also about how it's given to people, how it's
presented to the body. Exactly. It's a multifaceted
problem. And medicinal chemists, they play a
huge role in optimizing all those different aspects.
So it's like chemistry, biology, and a little
bit of like pharmaceutical engineering all rolled
into one. Exactly. You have to have a deep understanding
of how all these different pieces fit together.
You know how molecules behave in different biological
systems. It's fascinating. I can imagine. So
we've talked about robots and libraries of chemicals,
and then these really talented medicinal chemists
who are like tweaking and refining those molecules.
It's amazing to think about how much science
and creativity goes into just those. first few
steps of discovering a new drug. Yeah, it really
does lay the groundwork for everything else that
happens after. And I think it helps to explain
why it takes so long and costs so much to make
a new medicine. Right. Every single step is important.
From finding that initial hit to optimizing all
the different properties, it all matters. So
at the end of the day, what are the key takeaways
that you want our listeners to walk away with?
What should they really remember about this early
phase of drug discovery? Well, I think the first
thing is to remember that drug discovery is not
a straight line. You know, there's constant setbacks
and unexpected hurdles. There's a lot of trial
and error involved. Like navigating a maze. Right.
Every turn could lead to a dead end or new path
forward. Exactly. And the second thing is to
remember that it's not just about finding a molecule
that works against a disease target. Right. It's
about making sure that molecule can actually
become a medicine. You know, it has to be safe.
It has to be effective. And you have to be able
to actually give it to people. Right. So it has
to survive the journey through the body. actually
get to its target and then, you know, do its
job without causing a bunch of side effects.
Exactly. And that's where the expertise of those
medicinal chemists comes in. Right. They're the
ones that figure all that out. They're the unsung
heroes. They use their knowledge of chemistry
and biology to overcome all these challenges
and actually turn these promising hits into real
drug candidates. It's like taking a raw ingredient
and turning it into this delicious gourmet meal.
I like that. That's a great way to put it. So
last but not least, what else should people remember?
I think it's important to appreciate how collaborative
drug discovery really is. Okay. You know, it
takes scientists from all these different fields
working together to solve these really complex
problems. Yeah, like a team effort. Totally.
It really is a testament to human ingenuity.
Absolutely. And our drive to find better treatments
for diseases. Well, I have to say, this has been
so insightful. It's really cool to kind of get
this peek behind the curtain and see how all
these early steps in drug discovery really set
the stage for future breakthroughs in medicine.
I'm glad you enjoyed it. It's a field that often
goes unnoticed, but it's really the foundation
of everything we do in modern medicine. I agree.
Well, thanks for joining us on this deep dive
into the world of drug discovery. My pleasure.
Hopefully you learned something new and exciting
today. I hope so too. And until next time, keep
those brains buzzing. We'll catch you on our
next deep dive. See you then. Oh, yeah. Definitely.
There's this one project that really stands out.
It was a potential new treatment for Alzheimer's
disease. Oh, wow. And we had found this hit compound
that looked really, really promising. It had
really good activity against a key enzyme that
we think is involved in the disease. That's incredible.
So you had like this potential breakthrough on
your hands. What happened next? Well, the initial
tests, they revealed a pretty major problem.
the compound was being metabolized super fast
in the liver, like really fast. So basically
it was getting chewed up by the body before it
could even get to the brain where it needed to
be. Oh, that's such a huge setback. It's like
the compound was getting lost on its way to the
battlefield. Yeah, exactly. It was really frustrating.
But you know, it's actually a pretty common challenge
in drug discovery. Right. So. You know, what
do we do? We gotta put on our medicinal chemistry
hats and figure out how to fix it. So we started
exploring ways to tweak the compound's structure
to make it harder for the liver to break it down
so quickly. Okay, how do you even do that? I
mean, do you start changing things randomly until
something works? No, I wish it were that easy.
It's actually a really systematic process. So
we used computer modeling to predict how different
modifications would affect the molecule. Oh,
cool. And then we synthesized a bunch of different
versions of the compound, like each one with
just a tiny little change to the structure. OK.
And we tested each one in the lab to see how
they behaved. So it's like you're a molecular
architect, right? You're carefully redesigning
the building blocks of the compound. Yeah, that's
a great way to think about it. To make it do
what you want it to do. Exactly. And you know
what? It took a lot of tries, but we finally
found one that worked. Oh, wow. Yeah, after tons
of rounds of design and synthesis and testing,
we finally landed on an analog that was way more
stable in the body. That's amazing. And the best
part? It still had great activity against that
target enzyme. So you basically outmaneuvered
the liver. You outsmarted it. I guess you could
say that. Yeah. It was a huge win for the team.
But of course, that was just one hurdle down.
There's always more challenges to face before
this compound could actually move on to the later
stages of development. Right, of course. But
it's a great example of how crucial medicinal
chemistry is. You're taking this promising hit
and turning it into something that could actually
become a real drug someday. Yeah, exactly. It's
a challenging field, but it's also incredibly
rewarding. So we've talked about stability. What
are some of the other properties that medicinal
chemists need to consider when they're trying
to refine these hit compounds? Another really
big one is solubility. You know, the drug needs
to be able to dissolve properly in the body's
fluids. Okay. So it can be absorbed and reach
its target. Right. That makes sense. It's kind
of like when you try to dissolve sugar and water.
Some things dissolve more easily than others.
Exactly. And if a drug doesn't dissolve well,
it's not going to be absorbed as efficiently.
And that means it won't be as effective. Got
it. So how do you improve solubility? Well, medicinal
chemists can sometimes tweak the structure of
the compound to make it more soluble. Or they
can explore different formulations. Formulations.
What's that? Oh, it's basically how the drug
is packaged. You know, like, is it a pill? Is
it a capsule? Is it a liquid? All of those things
can affect how the drug dissolves and gets absorbed
in the body. Oh, that's interesting. So it's
not just about the molecule itself. It's also
about how it's delivered to the body. Exactly.
It's a really multifaceted challenge. And medicinal
chemists play a huge role in optimizing all those
different aspects. Wow. So it's like chemistry,
biology, and a bit of pharmaceutical engineering
all rolled into one. You got it. It's all connected.
You have to understand how all these different
pieces fit together, how the molecules behave
in different systems. It's really fascinating.
This has been amazing. I feel like we've gone
from like robots in these huge libraries of chemicals
to like the super detailed work of these medicinal
chemists who are like carefully correcting these
molecules. Yeah, it's been quite a journey. It
really has. And it's so cool to see just how
much like science and creativity goes into just
those first few steps of you know, trying to
discover a new drug. It really does lay the foundation
for everything that comes after. Yeah, and it
helps explain why it takes so long and costs
so much money to develop a new drug. Yeah. Right,
because every single step from finding that first
fit to making sure that I have all the right
properties, it all matters. Absolutely. Every
step is critical to making sure that we end up
with a safe and effective medicine for patients.
So at the end of the day, what are the key takeaways
that you want our listeners to walk away with?
What should they remember about this early phase
of drug discovery? Well, I think the most important
thing to remember is that drug discovery is not
a straight line. You know, there are always setbacks,
unexpected hurdles, lots of trial and error.
It's a really iterative process. It's like navigating
a maze. Every turn could lead you to a dead end
or like a new path forward. Exactly. And the
second thing to remember is that it's not just
about finding a molecule that works against a
disease target. It's about making sure that all
a cure can actually be turned into a medicine
that is safe and effective and practical to give
to people. Right. So it has to survive the journey
through the body, actually reach its target and
do its job. without causing a bunch of side effects.
Exactly. And that's where the expertise of those
medicinal chemists is so essential. They're the
ones who figure all that out. Yeah, they really
are like the unsung heroes of drug discovery.
Absolutely. They use their knowledge of chemistry
and biology to overcome all those challenges
and turn those promising hits into actual drug
candidates that can be tested and potentially
move forward. It's like taking a raw ingredient
and turning it into like a delicious gourmet
meal. That's a great analogy. And last but not
least, is there anything else that's important
for people to remember? Oh, I think it's also
important to appreciate how collaborative drug
discovery is. It takes scientists from all these
different fields working together to solve these
really complex problems. Yeah, it's a real team
effort. It really is. It's a testament to human
ingenuity and our desire to find better treatments
for diseases. I completely agree. Well, this
has been so insightful. I feel like we've really
gotten a glimpse into this world of drug discovery.
and how those early steps are so crucial for
medical breakthroughs. I'm glad you found it
interesting. It's a field that often goes unnoticed,
but it really is at the heart of modern medicine.
Well, thanks again for joining us on this deep
dive into drug discovery. We hope you learned
something new and exciting today. And until next
time, keep those brains buzzing. See you next
time. We'll catch you on our next deep dive.