3 - From Idea to Target Selection (S1E3)

Welcome back to The Deep Dive. Today, we're going
to be tackling the fascinating world of drug
discovery. Oh, very cool. Specifically, that
initial spark of an idea. OK. And the journey
from, you know, wouldn't it be cool if? Right.
To actually pinpointing a target for a new medicine.
It's a bit like setting out on an expedition,
you know? You know, you want to discover something
valuable. Right. But first, you have to choose
the right terrain to explore. OK. I like where
this is going. Yeah. So we're talking about the
very early stages, even before scientists start
tinkering in the lab. Exactly. Our source material,
pharmaceutical product development, in vitro.
in vivo correlation, right, emphasizes the crucial
role of unmet medical needs and deep biological
insights in shaping these initial steps. You've
piqued my curiosity. Good. What kind of needs
are we talking about and how do they spark ideas
for new drugs? Well, imagine a disease with no
effective treatments or a treatment that's effective
but comes with a laundry list of side effects.
Oh gosh. Those are glaring needs that scream
for innovation. So it's like finding a problem
that's begging for a solution. Yeah. A medical
mystery waiting to be solved. Precisely. Okay.
Let's take digoxin. Okay. A heart failure medication.
Scientists knew it was effective, but also that
its absorption varied wildly depending on the
formulation. Interesting. That unmet need for
consistent delivery -fueled research into how
particle size affects digoxin's dissolution and
bioavailability. Fascinating. So recognizing
those unmet needs helps set the stage for drug
discovery. Yes. But how do scientists actually
go from a broad need to a specific target for
a new medicine? Think of it like choosing the
right lock to pick. Okay. First you need to understand
how the lock works, right? Okay, I'm following.
Okay. So in this case, the lock is the disease
mechanism and the key is the drug. Brilliant
analogy. Thanks. Scientists need to delve into
the intricate biological pathways behind a disease.
Pinpointing the molecules or processes that are
going haywire and contributing to the problem.
That's how they find potential drug targets.
It sounds like detective work at the cellular
level. Yes. Looking for those. molecular culprits.
It absolutely is. Take the antifungal medication
grusofolvin. It was initially plagued by poor
absorption. Oh wow. By understanding that the
drug itself wasn't the issue. But rather, it's
low solubility. Scientists were able to create
a micronized formulation that dramatically increased
its effectiveness. So it's not just about finding
a target. It's also about understanding the target's
quirks and how a drug might interact with it.
Exactly. Once potential targets are identified,
they need to be rigorously evaluated. Remember,
not all targets are created equal. So what makes
a good drug target? What are scientists looking
for? in this molecular lineup? Think of it as
a three -legged stool. Okay. Drugability, safety,
and efficacy. Okay, break that down for me. What
does it mean for a target to be drugable? A drugable
target is one that can be effectively modulated
by a drug molecule. Okay. Imagine trying to open
a lock with a key that's the wrong shape. It
just won't work. Oh, I see. Right. So the grug
needs to be able to fit the target and have a
real impact on its activity. Precisely. And of
course, safety is paramount. Right. Interfering
with the target shouldn't cause unacceptable
side effects. You don't want to fix one problem
only to create a host of new ones. Right. It's
like making sure the key doesn't accidentally
unlock a bunch of other doors and cause chaos.
Exactly. What about efficacy? Efficacy means
that hitting the target should have a real meaningful
impact on the disease. Okay. The key needs to
actually open the right door and lead to the
desired outcome. Finding a target that checks
all those boxes? drugable, safe, and efficacious.
That's gotta be like finding a needle in a haystack.
It's one of the biggest challenges in drug development,
no question. Scientists are constantly pushing
the boundaries using cutting edge technologies
and insights to sift through potential targets
and identify the most promising candidates. Wow.
Yeah. So finding those ideal targets is like
a high stakes treasure hunt with scientific ingenuity
as the map. I like that analogy. But let's dive
a little deeper into this idea of drugability.
Okay. What are some of the factors that determine
whether a target can actually be modulated by
a drug? That's a great question. Thanks. One
key factor is the target's structure. Think of
a drug molecule like a puzzle piece. Okay. And
the target, like a puzzle board. Right. For the
drug to work, it needs to fit snugly into a specific
spot on the target. So the target needs to have
a binding site. Yes. A pocket or a groove where
the drug can latch on. Exactly. Okay. And that
binding site needs to be accessible to the drug.
Right. If it's buried deep inside the target
molecule, the drug might not be able to reach
it. It's like trying to fit a key into a lock
that's hidden behind a wall. Right. No matter
how perfectly the key matches the lock, it's
useless if you can't get to it. That's a perfect
analogy. Another important factor is the target's
function. Ideally, you want to target a molecule
that plays a key role in the disease process,
something that's essential for the disease to
thrive. So it's like finding the weak link in
the chain, the Achilles heel of the disease.
Precisely. And you want to make sure that hitting
that target will have a significant impact on
the disease, ideally stopping it in its tracks
or at least slowing it down. But how do scientists
actually figure out which targets are worth pursuing?
Right. It seems like a daunting task sifting
through all those molecular suspects. It is a
challenge. But thankfully, scientists have a
growing arsenal of tools and technologies to
help them. OK. One powerful approach is high
throughput screening. High throughput screening.
What's that? Imagine a giant library filled with
millions of potential drug compounds. Oh, wow.
Each one slightly different from the next. High
throughput screening allows scientists to test
these compounds against a target. in a very rapid
and automated way. So it's like speed dating
for drugs. Uh -huh, yeah. Trying to find the
perfect match for the target. That's a fun way
to think about it. Yeah. And once they've identified
some promising hits, they can then start to optimize
those compounds, tweaking their structure to
improve their binding affinity, their potency,
and their overall drug -like properties. It sounds
like a process of refinement. Yes. Starting with
a rough diamond and carefully shaping it into
a brilliant gem. That's a beautiful analogy.
And of course, throughout this entire process,
safety is always top of mind. Scientists are
constantly evaluating the potential toxicity
of these compounds, making sure they're not causing
harm while trying to do good. So it's a delicate
balancing act, trying to maximize efficacy. while
minimizing risk. Exactly. And it's a process
that requires incredible precision ingenuity
and a deep understanding of both biology and
chemistry. Okay, so we've talked about unmet
medical needs, the characteristics of good drug
targets, and the tools scientists use to find
and refine those targets. But our source material
also mentioned something called the biopharmaceutics
classification system, BCS. How does this fit
into the picture? The BCS is a brilliant system
that helps us understand how a drug's properties
influence its journey through the body, specifically
how well it gets absorbed from the gut into the
bloodstream. So it's like a roadmap for drug
absorption, helping scientists predict how a
drug will behave based on its inherent characteristics.
Exactly. The BCS classifies drugs into four categories
based on their solubility and permeability. Solubility,
as we've discussed, is how well a drug dissolves
in fluids, and permeability is how easily it
crosses biological membranes. Right, those are
two key hurdles a drug needs to overcap to get
into the system. Absolutely. Class I drugs are
the superstars. High solubility and high permeability.
They dissolve easily and zip across membranes
without a hitch. So those are the drugs that
have an easy time getting absorbed. No special
tricks needed. You got it. Great. Then we have
class II drugs, which have Low solubility, but
high permeability. They can cross membranes readily,
but their absorption is limited by how well they
dissolve. So it's like having a sports car with
a flat tire. It has the potential for speed,
but it needs a little help to get rolling. That's
a great analogy. Thanks. And this is where formulation
strategies become crucial for class II drugs.
OK. Scientists can use techniques like particle
size reduction or special excipients to boost
their solubility and improve their absorption.
So it's like giving that sports car a new set
of tires allowing it to reach its full potential.
Precisely. OK. Then we have class III drugs.
OK. High solubility but low permeability. They
dissolve well. But they have a harder time crossing
those biological barriers. So it's like having
a key that fits the lock but can't quite turn
it. It needs an extra push to unlock the door.
Exactly. And in this case, scientists might explore
strategies like permeation enhancers, substances
that can temporarily increase the permeability
of membranes, giving those class III drugs a
helping hand. It's like lubricating the lock,
making it easier for the key to turn. Perfect
analogy. OK. And finally, we have the class IV
drugs. OK. low solubility and low permeability.
They face an uphill battle on both fronts, making
them the most challenging to work with. It's
like having a rusty key that can't quite fit
a stubborn lock. You need a whole toolbox of
tricks to get that door open. That's a great
way to visualize it. Developing effective formulations
for class IV drugs often requires a combination
of strategies. And even then, achieving adequate
absorption can be tricky. So understanding the
BCS classification is like having a cheat sheet
for drug absorption. Yeah. Helping scientists
anticipate potential hurdles and design strategies
to overcome them. Absolutely. OK. It's a powerful
tool that helps guide the development process
and ensures that scientists are choosing the
right approaches for each drug. Right. Ultimately
increasing the chances of getting effective treatments
to patients. OK. So we've explored how unmet
needs spark drug discovery. Right. the intricate
process of target selection, and the importance
of understanding drug properties through the
BCS. But our journey isn't over yet. There's
one more fascinating area we need to delve into,
in vitro, in vivo correlation, or IVIVC. IVIVC,
the bridge between the lab bench and the human
body. It's like having a crystal ball. OK. That
helps us predict how a drug will behave in the
real world based on its performance in laboratory
tests. That sounds incredibly powerful. But how
does it actually work? How can we connect the
dots between what happens in a test tube and
what happens in a living, breathing person? It
all starts with dissolution testing, which we've
touched upon already. Remember, dissolution is
the process of a drug dissolving in a fluid,
like those found in our gastrointestinal tract.
It's a crucial step for absorption, as a drug
needs to dissolve before it can enter the bloodstream.
It's like making a cup of tea. The tea leaves
need to infuse into the hot water before you
can enjoy the flavor. Exactly. And just like
you can control the strength of your tea by adjusting
the brewing time. Scientists can assess the rate
and extent of drug dissolution using carefully
controlled laboratory tests. So these tests help
us understand how quickly and completely a drug
dissolves outside of the body. Yes. Giving us
clues about how it might behave inside. Precisely.
And here's where IVIVC comes in by comparing
dissolution data from these in vitro tests with
data from in vivo studies like clinical trials.
We can build a predictive model. So it's like
finding a pattern. Yes. A correlation between
how a drug dissolves in the lab and how it gets
absorbed in the human body. You got it. OK. And
the stronger that correlation, the more confident
we can be in predicting a drug's performance
based on its dissolution profile. This has huge
implications for drug development. OK, I'm seeing
the potential. So how does IVIVC actually help
scientists create better medicines? In several
ways. First, it can help optimize drug formulations.
By understanding how dissolution influences absorption,
scientists can fine -tune the composition of
a drug product to achieve the desired release
profile. So if a drug is dissolving too quickly
or too slowly, they can tweak the formulation
to get it just right. Exactly. Cool. IVIVC can
also play a role in reducing the need for certain
clinical trials. Really? If we have a strong
correlation between in vitro and in vivo data,
some bioequivalence studies might be waived.
bioequivalent studies. Those are the ones that
compare generic drugs to brand name drugs. Yes.
To make sure they work the same way, right? That's
right. And if we can demonstrate bioequivalence
through dissolution testing alone, it can save
time and resources, ultimately getting those
generic medications to patients faster. That's
a win for everyone. less expensive medications,
and a faster path to market. Exactly. Are there
any examples of how IVIVC has been used to improve
real -world drugs? Absolutely. Remember that
heart failure medication digoxin we talked about
earlier? Its bioavailability can vary significantly
depending on how quickly it dissolves. By establishing
an IVIVC model, scientists were able to develop
a formulation with more consistent dissolution,
leading to more predictable therapeutic effects.
So IVIVC helped create a more reliable and effective
treatment for heart failure patients. Yes. That's
incredible. It's a testament to the power of
understanding drug properties and their impact
on the human body. Wow. And, you know, as we
wrap up this deep dive. Yeah, I'm struck by the
intricate web of knowledge that underpins drug
development. I know what you mean. We've journeyed
from unmet needs to target selection. Right.
From the complexities of drug properties to the
predictive power of IVIVC. Uh -huh. It's a remarkable
process that blends scientific ingenuity with
a profound commitment to improving human health.
It truly is. Wow. And at the heart of it all
is the desire to alleviate suffering to extend
lives and to empower people to live healthier
and more fulfilling lives. So the next time you
take a medication... Remember the incredible
journey it took to get there. Yes. From the initial
spark of an idea to the rigorous testing and
refinement, it's a testament to the boundless
potential of human curiosity and the unwavering
pursuit of a healthier world. Absolutely. Thanks
for joining us on this Deep Dive.