23 - Drug-like Properties & ADME (S2E8)

All right, so let's dive into this drug development
stuff. You sent some fascinating sources about
what makes a molecule drug -like. And a lot of
it seems to have something to do with ADME. Yeah,
ADME. It's a pretty fundamental concept. It stands
for absorption, distribution, metabolism, and
excretion. So basically what our bodies do to
a drug once it's inside? Exactly. It's figuring
out the journey a drug takes once it enters the
system. Makes sense to study it early on, too.
For sure. You wouldn't want to spend years developing
a drug that just disappears from the body immediately.
Right. Or even worse, turns into something harmful.
One of the sources mentioned metabolic stability
is being super important. Yeah. So during lead
optimization, they're screening those drug candidates,
checking how they break down and how long they
stay in the system. Like a molecular obstacle
course? I like that. A lot of it is done in vitro,
too, outside a living organism. So not in a person
or an animal? Right. They use things like liver
microsomes. What are those? Think of them as
mini -livers in a test tube. Wow. So they're
recreating what happens in our bodies, but in
a more controlled environment. You got it. It
gives them a sense of how stable a molecule is
if it breaks down too fast. Well, it's back to
square one. Pretty much. Yeah. But one of the
articles mentioned that sometimes a drug breaking
down quickly can actually be a good thing. Really?
That seems counterintuitive. It comes down to
the metabolites. Which are? the products that
are formed when a drug breaks down. OK. And sometimes
those metabolites are pharmacologically active
themselves. You mean they can have effects just
like the original drug? Sometimes even better
therapeutic properties than the original molecule.
Like a bonus price. Exactly. But you know, there's
also that darker side to metabolism, too. Right.
Something about reactive metabolite. Unfortunately,
yeah. While some are helpful, others can be problematic.
Problematic how? They're unstable and they can
interact with our cells and cause damage. So
that's where you get those side effects in toxicity.
Liver toxicity, DNA damage, triggering immune
responses. That's why understanding what those
byproducts do is so crucial. Catch those red
flags early. I see. It's amazing how a drug just
Breaking down has a huge impact. It's a delicate
balance. So how do scientists even predict whether
a molecule will be absorbed well in the first
place with all these different aspects of ADME?
Well, they use certain guiding principles. One
of the most famous is Lipinski's rule of five,
kind of a cornerstone of medicinal chemistry
for decades now. Lipinski's rule of five. What's
the significance of the number five? Not magic,
but it's based on observations about the characteristics
of successful drugs. So for a molecule to be
absorbed easily, it shouldn't break too many.
of these rules, molecular weight less than 500,
no more than five hydrogen bond donors, no more
than 10 hydrogen bond acceptors, a certain level
of greasiness, which is measured as log P, and
that should also be less than five. OK, so these
are like guidelines to predict how well a drug
will get into the bloodstream. Exactly. It's
a filter for weeding out molecules that are unlikely
to be absorbed well. You know, it might have
great activity in the lab, but if it can't even
reach the bloodstream. It's not going to be very
useful. Right. So are there exceptions to this
rule? Sure. Especially with all these new therapies
coming out. You're talking about things like
biologics. Like antibodies. And protechex, which
work completely differently. Lipinski's rule
doesn't always apply. So these newer drugs are
playing by a different set of rules, though.
What makes them so unique? Myologics, for instance,
they're much larger molecules than the typical
small molecule drugs that Lipinski was thinking
about. They work by binding to very specific
targets, usually on the surface of cells. Interesting.
So it's less about being absorbed into the cell
itself, but more about interacting with it from
the outside. Exactly. Highly specialized keys
fitting into specific locks on the cell's surface.
And their size, which would normally be a disadvantage,
according to Lipinski, actually works to their
advantage. Fascinating. What about pro -tax?
How do they bypass these rules? Pro -tax are
really interesting. They act like molecular matchmakers.
They bring together a target protein and the
cell's own protein degradation machinery. It's
like hijacking the cell's natural cleaning system.
A Trojan horse. Exactly. To get rid of those
harmful proteins. And because they're designed
to be recycled within the cell, they don't need
to follow the same absorption and distribution
rules as conventional drugs. I see. So they work
from the inside out. You got it. This is amazing.
Drug development is really pushing the boundaries.
Yeah. But even with these exceptions to the rule,
scientists still need to understand how these
new types of drugs are distributed, metabolized,
and eliminated from the body. Of course. It's
not a free pass just because they're unconventional.
You need the whole picture. How it gets in, where
it goes, how it breaks down, how it leaves. And
that's where those early ADMetox models and high
throughput testing come in. Okay, so tell me
more about that. Well, that's a whole other story.
Yeah, it's not a free pass. You're right. You
still have to understand those key aspects, even
with these groundbreaking drugs. So how are scientists
tackling this? Especially early on in development,
you mentioned ADMetox models. What are those?
They're like a sneak peek into the future of
a drug candidate. You get a glimpse of how it
might behave in the body way before human trials.
So like a crystal ball for drugs. But how can
they predict what will happen in something as
complex as the human body? No model is perfect,
but they give you really valuable insights. Some
of them use computer simulations. They're getting
so sophisticated now. So it's like those personalized
recommendations you get online, but for molecules.
Kind of. They consider so many factors, potential
drug interactions, genetic variations. It's pretty
amazing. That's incredible. What about those
mini -organs I read about, the organoids? How
do they fit into all of this? Organoids are really
changing the game. They give us a more realistic
system to study drug effects compared to traditional
cell cultures. So it's like a miniature version
of an organ in a dish. Exactly. You can actually
see how a drug is absorbed, distributed, metabolized,
even assess its toxicity. It's a much more accurate
picture. Wow. That's pretty sci -fi. Sounds like
these models are really bridging the gap between
the lab and the real world. But even with all
these advances testing, each potential drug must
still take a lot of time. Right. You mentioned
high throughput testing earlier. How does that
speed things up? Imagine a bunch of tiny robots
working nonstop, testing thousands of compounds
at the same time for very specific properties.
That's high throughput testing. It really accelerates
the screening process, especially for ADME. Like
a cooking show with tons of ovens going at once.
Yeah. And instead of food, they're making data.
I like that visual. And one of the key things
they test is permeability. how easily a drug
can get across cell membranes, it's crucial for
it to reach its target. It's the ultimate test
for these molecules. And with high throughput
testing, scientists can quickly identify the
winners. The molecules that can be absorbed well,
they weed out the ones that don't make the cut.
So it's about being efficient and strategic with
your testing. Exactly. And by combining these
advanced models with fast screening methods,
it really streamlines the whole drug development
process. It's amazing how far things have come.
What are your thoughts on where this is all heading?
It's a very exciting time to be in this field.
It's not just about speed. It's about precision,
too. We're moving away from that one size fits
all approach to medicine and tailoring treatments
for individual patients based on their genes
and other factors. So personalized medicine,
but on a whole other level. Exactly. And understanding
ADME is at the heart of this whole shift. If
we can predict how a drug will behave in different
people, we can develop safer and more effective
therapies. That's incredible. We've covered a
lot today. Anything else that you think is important
for our listeners to take away? I'd emphasize
the importance of research and innovation in
ADME. As we make new types of drugs and learn
more about the human body, our understanding
of ADME has to keep up. So it's not a static
field. It needs to keep evolving, just like drug
development itself. Exactly. And this ongoing
research will lead to better models and testing
methods, refining our ability to predict how
a drug will behave in the body. It's about minimizing
risks and maximizing the chances of success in
drug development. It's fascinating how something
seemingly simple like what our bodies do to a
drug can be so complex. Yeah, it really shows
how much teamwork goes into drug development.
It's not just one person in a lab. It's chemists,
biologists, pharmacologists, even computer scientists,
all working together. It really does take a village.
And ADME is such a critical part of that whole
process. Because at the end of the day, it comes
down to that one question. Will this molecule
actually be a good medicine? Exactly. And it's
not just about showing it works in the lab. You
need to understand how it's absorbed, how it
moves through the body. how it's broken down,
how long it lasts, and are those breakdown products
safe? It's like tracking the molecule's journey
through the body with all its twists and turns.
And the more research we do, the clearer that
picture becomes. That's leading to some really
amazing advancements in medicine. Safer, more
effective, and more personalized treatments.
Exactly. It has the potential to really revolutionize
health care. But there are still a lot of questions
that need to be answered. What would you say
are some of the biggest challenges in ADME research
right now? One area that's really exciting is
the role of the microbiome in drug metabolism.
The microbiome. You mean the bacteria that live
in our gut. Exactly. We're just starting to understand
how those trillions of bacteria can affect how
our bodies process drugs. So it's not just about
human enzymes anymore. Right. It's a whole ecosystem
in there. And it can vary a lot from person to
person. So scientists are trying to figure out
how these microbes contribute to drug metabolism
and whether we can use that knowledge to make
drugs even better and safer. That's fascinating.
It's like our bodies are these incredibly complex
worlds with so many factors influencing our health.
It really is. And the more we learn, the more
we realize how much we don't know. It sounds
like there's still so much to discover. Well,
I think we've covered a lot of ground today and
it's time to wrap up this deep dive. Yeah, we've
only scratched the surface of this really complex
and constantly evolving field. But hopefully
our listeners have a better appreciation for
ADME and how important it is in drug development.
Absolutely. Those questions about absorption
distribution, metabolism, excretion, they might
seem simple. but they have huge implications
for the medicines of the future. It's been a
really fascinating conversation. Thank you for
joining us today. It was my pleasure. Thanks
for having me. And all our listeners out there,
thanks for tuning in. We'll be back soon with
another deep dive into the world of science and
technology.