Hello everyone, we will continue on the course
on Computer aided drug design.
We will talk about some of the issues in the
drug discovery process.
So let us recap; drug discovery is a process
by which a drug candidate is identified, and
partially validated for the treatment of a
specific disease.
So as I said partially validated, because
it becomes a drug, only after it gets approval
from FDA that, is the food and drug administration
of USA.
So in order to get approval you need to go
through all the various preclinical trials
involving animals and then human volunteer
trials, so until then it is called as a lead
molecule.
So in my lab I may get a nice candidate which
looks very promising, which shows very good
activity in my activity screen, maybe anti-inflammatory
activity or anti-cancer activity, so I call
that as a hit molecule, and then I go and
finally 0 in 1 candidate, I call it as a lead
molecule, and the lead molecule is what is
being tested in the preclinical clinical trials,
and this lead molecule should have not only
the activity but other properties which we
are going to spend a lot of time on.
So the drug discovery we need to understand
the mechanism of action, we need to identify
the target which target or enzyme or protein,
it is going to go and bind to, and inhibit
it or inactivate it.
We need to validate that target, and then
we need to optimize the lead, so there could
be 1 possible candidate which looks very promising.
So we may have to change some of its properties,
so that it increases solubility maybe the
toxicity is reduced, side effects is reduced,
that is what is called lead optimization.
And it should satisfy all the ADME properties.
Yesterday I mentioned A is absorption, D is
distribution, M is metabolism and E is excretion.
So it should get absorbed very nicely into
the human system, absorb as we can say, and
then comes distribution into the bloodstream,
maybe it gets distributed into the various
tissues, then it should it be getting metabolized,
and then finally once it has done its job
it should get excreted that is also very important.
So it should satisfy these ADME properties,
and then it should have good pharmacokinetics
and pharmacodynamics property.
Yesterday I did talk about pharmacokinetics
and pharmacodynamics.
So all these, and then of course, it should
not have any toxicity, all these are very
important.
So in the drug discovery we are not going
to talk about preclinical studies, clinical
trials, regulatory approvals, sales marketing
and so on.
These are not part of the drug discovery process.
So it is a very long process, it involves
a lot of money as you can see here, in silico,
when we say in silico we use computational
tools okay that is called in silico.
In vitro means we use laboratory biochemical
assays, proteomic assays that is called, in
vitro.
When we say in vivo it means using animals,
so there are 3 terms in silico that is the
term here which talks using computational
tools okay.
In vitro is laboratory studies, and then in
animal studies is always called in vivo.
So there are 3 types of terminologies which
we use.
So the in silico takes 2 to 3 years may cost
about 10 million, then we go to testing on
animals that is the in vivo, in between you
may you will also have the in vitro also that
may take another one year or more it may cost
10 million dollars> Then we go through the
various human voluntary trials okay phase
1, phase 2, phase 3.
Again you can see 1 year, 1 year maybe 3 years,
and these are the cost factors, so finally
it may add up to almost a billion US dollar
that is the current cost of manufacturing
sorry current cost of introducing a new molecule
into the world.
So it is a very expensive process and this
is taken from this particular reference here.
So as you can see synthesis, extraction if
you are a chemist maybe synthesizing a new
molecule.
If you are using natural products maybe extracting,
and then we are going test it against maybe
anti-cancer drug or anti-inflammatory drug
or diabetic related.
So biological testing, then you have toxicological
studies, pharmaceutical dosage formulations.
Then comes the clinical trial clinical evaluation
that is on the human.
And then phase 4 trials.
Process development, because you need to manufacture
in large quantity, then we need to get approval
from the regulatory authority, looking at
bioavailability and so on actually.
So if you look at this cost factors clinical
trials contributes to 25% and so on, then
we are going to regulatory, authorities and
that also going to cost a lot of money, biological
screening 12%.
So it is an expensive process, that is why
when a drug is introduced, a new drug is introduced
into the market it will be very expensive,
because cost of introducing a new drug from
the lab is a very expensive process.
So if you look over a period of time the cost
keeps increasing the R and D cost keeps increasing,
but the new chemical entities are sort of
decreasing that is because the FDA has become
more stringent, they want more information
they want to know what are the side effects
and they want to know that long term toxic
effects of the chemical the toxic effect of
the metabolized products.
So that is why the cost is going up and many
compounds do not succeed and cross the FDA
barrier.
And that is a big problem nowadays in drug
discovery that is a big challenge.
So this is the very interesting slide, so
it may cost about 1 billion or even 1.2 billion
US dollars to launch one drug molecule in
the market, that is a new drug I am talking
about, if it is already old and you want to
use that particular drug for some other disease
that is called repurposing.
For example, aspirin, aspirin was originally
introduced for fever then pain later on aspirin
is being used quite a lot for blood thinning
purpose,, that is called repurposing that
will not cost you much.
So it takes about 12, 15 years for 1 new drug,
so it is a very long process as you can see
very long process.
We start with some computational studies here,
that is the computational biology studies
we decide on the disease, what type of disease
you are looking?
Are you looking at inflammation? are you looking
at cancer, certain colorectal cancer or breast
cancer?
So which target I am going to look at , so
I need to identify which target.
Because there could be many enzymes, proteins,
molecules are involved, and your drug maybe
working only one particular target, so I try
to identify which target.
Once you have identified the target you start
designing molecules and that is what is called
a lead identification, once you have decided
go for lead identification.
So there are a lot of techniques involved
if you want to look at the disease mechanism.
How does say an inflammation progresses, starting
from the site of inflammation right down to
various leukotrienes or prostaglandins, so
what are the various enzymes involved, how
is the metabolic pathway, so I can use computational
biology type of approach, draw a big network
of various pathways, and then I can see how
the flux flows, so that is called a computational
biology.
If I want to identify the protein, if I want
to identify the protein, then I may use proteomics
tools.
We will talk little bit on proteomics, but
I will not talk too much on that trying to
identify the protein structure, 3 dimensional
structure its function and its active site
that is all called proteomics.
You may have to use some bioinformatics tools,
because we may have to compare the protein
which you have isolated for your disease,
are there similar proteins available the databases.
What are the properties of those proteins,
so I can connect with the new unknown protein,
that is called bioinformatics.
Then the actual discovery of the lead which
involves, molecular modeling, quantitative
structure activity relationship, QSAR means
quantitative structure activity relationship.
We are going to talk quite a lot about this
particular portion, and then we need to do
the wet lab experiments that is experiment
in your lab.
That is where you check the biological activity
of your compound, you may use bacteria, you
may use virus, you may use animal cells whatever
is your biological assessment.
Simultaneously, I need to understand the properties
of the compound, the lead drug likeness, does
it have the drug likeness properties, that
means after all it is going to be consumed
by human, so it should not have certain problems.
Or it should have certain properties like
good solubility, good absorption that is called
drug likeness property.
Does it have toxicity short term toxicity
long term.
How is it ADME we keep on introducing this
term ADME it is going to come quite often
now, does it have good ADME properties?
So simultaneously, when we are looking at
possible candidates and testing it out in
the wet lab biological assays I need to understand
these things also, this is very, very important.
Because many drugs may have good activity
but they may be very toxic.
Many leads may have very good activity but
in the stomach it gets degraded, because as
you know the stomach pH is extremely acidic
pH of 2.
It may have good activity maybe it is toxic,
but may have good activity or maybe it gets
metabolized inside by liver and the other
enzymes involved, so the active drug concentration
may be very, very less at the target site.
So the ADME could be very poor, the absorption
could be poor, the distribution inside could
be very poor, and it gets metabolized so concentration
is very poor, or it does not get excreted
from the body, so it keeps staying inside,
it gets accumulated and over long period of
time the concentration maybe very high which
may be toxic.
For example, if I am using nanoparticles metal
nanoparticles they may stay inside the body
get absorbed by the tissues, because they
are nano size.
And they have metal toxicity that is why now
use of metal nanoparticles in the body there
is a lot of worry, because of this particular
problem.
So simultaneously when we look at a lead an
active molecule, we may have to simultaneously
look at all these.
I may have to perform experiments to determine
all these parameters, or I can use computational
tools to predict some of the drug likeness
property, toxicity, ADME and so on.
So the course is predominantly going to cover
this molecular modeling QSAR, course is going
to cover prominently some of these computational
approaches for determining ADME and drug likeness
property.
So of course simultaneously one has to see
how to manufacture the drug in large quantities
that is called process development bio-process,
and it should have the good manufacturing
practices approved by FDA and so on.
Once a lead is identified it goes through
the animal preclinical trials then clinical
trial 1, 2, 3 and then FDA approval and finally
gets launched.
So this is the pipeline for new drug discovery,
so here we are talking quite a lot about computational
approaches computational biology, proteomics,
bioinformatics.
Here we have the molecular modeling, and then
here we have the drug likeness, ADME prediction
okay.
So the course is going to cover these 2 circles,
how computers can be used for measuring not
measuring calculating some of the parameters
that is what we are going to talk about okay.
So the drug discovery/development process.
we can call it the discovery stage, the development
stage, the registration stage.
Discovery like I said target identification,
validation we need to develop the assay.
For example if I am going to study how my
drug is going to bind to a protein or enzyme
and inhibit I should have a biochemical assay
okay, maybe a fluorescence assay or a calorimetry
assay or a radioactive assay or I may use
an animal cell, I may be looking at some metabolites
that are produced.
So assay development is also very, very important.
Then once I identify my lead I need to optimize
the lead, that means it is the balance between
activity vis-a-vis its properties.
So that is called lead optimization.
Then the pre development.
Of course the development stage we have the
animal studies and clinical studies.
And then of course registration regulatory
approval looking at the life cycle.
Sometimes drugs after being introduced into
the market may be withdrawn, because certain
things which have not been thought of it may
have been having problems actually, that is
why phase 4 is like getting feedback from
the people who have been using the drug globally
or in particular continent, and then see if
there are any problems which has not been
thought of.
For example, there are many drugs, we have
the anti-inflammatory, selective Cox 2 inhibitor
which was introduced into the market, and
then it was withdrawn because it had cardiovascular
issues on some of those patients who took
that.
So phase 4 is also very important which is
like a follow up, but as I said our focus
is more on the side of it and nothing to do
on that side okay.
So but still we need to understand little
bit on phase 1, phase 2, phase 3 and phase
4.
So there are 4 different phases of operation,
phase 1 involves human pharmacology, phase
2 involves therapeutic exploratory, phase
3 involves therapeutic confirmatory, phase
4 like I said post marketing after it has
been marketed.
The phase 1 we are looking at any side effects
that may be caused by the drug when it is
given to healthy volunteers.
And phase 2 is looking at what is the dose
response, if I give 1 milligram what is the
response.
For example, it is bacterial like an antibiotic,
if I give 1 milligram how much bacteria is
killed, if I give 2 milligrams how much bacteria
is killed, so that is called therapeutic exploratory.
Then in phase 3 we are looking at long term
side effects that is why it is done for 3
years and so on actually okay.
So phase 1 we are looking at tolerance, we
are looking at pharmacokinetics and pharmacodynamics,
that is a very important thing that happens.
Pharmacokinetics is when the drug is given
to a patient, gets a little bit absorbed then
it gets excreted so in how many hours does
it get excreted.
What is the maximum concentration of drug
in the body because of the metabolism and
absorption?
So that sort of parameters is determined in
pharmacokinetics, so you may take a sample
either from the blood or target site and see
what is the concentration of the drug and
so on.
In pharmacodynamics what the drug does to
the patient or the target?
So if the drug is there, does the bacteria
go down 10%, does it go down 20% or if you
are looking at a tumour the tumour size goes
down as a function of drug concentration.
So pharmacokinetics is what the body does
to the drug, pharmacodynamics is what the
drug does to the body.
You also look at drug metabolism and drug
interactions, and also estimate the activity.
In phase 2, you look at where the drug goes
on acts, so you try to look at whether there
is up-regulation and down-regulation of the
target, what is the dosage required to kill
a particular amount of bacteria or reduce
the activity of some protein?.
So we develop something called dose response
curve.
So if this is the concentration of the drug
what is the response?
So initially for some concentration there
won’t be much response of the drug, the
fever goes down by 1 degree Fahrenheit.
If I give 2 milligram fever goes down by 5
degree Fahrenheit.
So that is called a dose response curve, that
is what you measure in the phase 2.
This also helps you to identify the endpoints.
When do you stop giving the drug , so do I
stop and when the temperature comes down to
somewhat certain value, do I stop for an infection
when the amount of infection or bacteria is
less than 5000 like that is called the endpoints.
So all these are measured in phase 2.
Then the phase 3 we are looking at safety
profiles.
That is a very, very important point in phase
3 the safety profiles, look at the benefit
of the versus risk.
Because there are cancer anti-cancer drugs
which could be very toxic to the healthy cells,
but at the same time they may be killing the
cancerous cells.
So we look at the benefits versus risk okay.
If there is terminally ill patient and the
patient will not survive more than six months.
So by giving the drug which may be toxic patient
may survive for 2 years, so it is worth it,
so that sort of studies we do actually, we
do all these things in phase 3.
Then of course phase 4, is after it is being
marketed, is there are any other adverse reactions;
do I have to again give some warnings to people
who are taking the drug after all in the phase
1, phase 2, phase 3 trials the drug is tested
only for about 1000 volunteers, but then when
it is given to public at large there could
be some new reactions which has not been thought
of okay, so that is done in phase 4 trials.
So drugs fail, lot of drugs fail very little
lead compounds get converted as a new drug
enters market lot of drugs fail , why do they
fail?
Okay.
As you can see 9 out of every 10 new drugs
failed in clinical testing, 9 out of 10 that
means the success is 10% or even less.
The drug in phase 3 testing has 32% chance
of failure, that means it is crossed phase
1, it crossed phase 2, but still it can fail.
Because it has crossed phase 1 and phase 2,
the percentage failure rate is much lower
when compared to this right, here the success
is only 10% or 90% failure.
Once it has crossed phase 3 success the failure
percentages is only 30%, because at each phase
the pharma companies spend millions of dollars.
So if the drug fails and it has to be withdrawn
they have lost lot of money.
So only 20% of drugs that enter phase 1 make
it to the market, that means remaining 80%
failed, so whatever money they have spent
goes down the drain.
So that is why the computation tools are being
widely used so that we try to find out failure
possible failure compounds and do not take
it further.
Phase 1 50% fail, phase 2 30% and phase 3
25 to 50%, so overall success rate is 3 to
8%, so like I said here 10%.
And the percentage of drugs failed for neurological
disease is higher okay, because neurological
diseases are much complicated, the drug has
to enter the brain region and then do its
job.
Whereas remaining drugs like inflammation
or cancer or stomach pain or fever they do
not have to go to the brain region, so the
requirements are very different so that is
why percentage of drugs failed for neurological
disease is higher..
200 candidates failed for Alzheimer disease
in clinical testing, Alzheimer's disease is
more to do with the loss of memory and so
on.
But they are being tested in rats or mice
that means preclinical trials they work, but
when it comes to human volunteer trial it
fails.
Of course there is a difference between the
system of rats, mice versus human.
But still rats and mice are used widely in
preclinical trials, because they are the closest
to human, and they are much cheaper okay.
So many drugs stopped working and tested in
people, why is that?
Maybe toxicity, maybe when it was tested in
animal slight elevation of some liver enzyme,
which was not taken very seriously, but when
it was given to human the enzyme level may
be getting elevated too much.
Even if there is one random fluctuation in
100s of test, then they decide that drug is
not very safe and it has to be withdrawn,
1 in 100 okay, that is very, very tough business.
Poor biopharmaceutical properties like I mentioned
solubility is very poor, maybe absorption
is poor, metabolism is happening either in
the stomach or in the liver region, because
of various enzymes present.
It is not getting excreted properly or it
gets excreted very fast.
It is not getting distributed too much that
means the concentration of the drug in the
blood is so low, all these 39%.
Lack of efficacy, that means the concentration
at the target site is not sufficient.
Imagine I have a pain in my finger and I take
a drug called Ibuprofen, I am sure all of
us would have taken Ibuprofen okay.
So the drug is taken orally, so we have the
GI that is the gastrointestinal, then it gets
absorbed into the blood, then you also have
these liver enzymes which keeps degrading
this, then it is wasted, and then finally
it reaches the target.
If it does not get absorbed properly from
GI again it gets wasted through the faeces.
If the liver degrades this it comes out through
the urine, again it is waste so finally it
reaches the target.
So the concentration of the drug in the target
is much, much less than the concentration
of the drug taken by us orally.
So it might not be sufficient to perform its
duty.
For example, if I am looking at an antibacterial
drug, the concentration of the drug should
be sufficiently larger than the minimum inhibitory
concentration of the bacteria it is called
MIC.
So the concentration of the drug in the target
site is very, very low, that drug is of no
use that is called lack of efficacy okay understand.
Then toxicity the drug has toxicity or the
metabolites, the drug gets degraded in the
liver maybe those metabolites are toxic, short
term toxicity long term toxicity, so 21%.
So you see if you add all these 39, 29, 21
it is a huge number, and so the properties
of the drug are very, very important okay.
The ADME properties, the efficacy as we can
see which I explained here, because of lack
of efficacy, then of course toxicity many,
many drugs fail during the development process
either preclinical or clinical trials.
So one need to put in a lot of focus in this
area not only just looking at the activity
in my lab, anti-cancer activity is showing
very good activity against certain cell lines,
but I need to also understand the physicochemical
properties of the molecule.
And also so that I can design a molecule which
satisfies all these condition in addition
to good activity, so that is very, very important.
So a drug is not only doing very well in the
lab because it is showing a very good activity,
but it should also have all the properties
okay the biopharmaceutical properties, and
also this good efficacy, so that it passes
the clinical trials and it gets approved .
That is why we are going to spend a lot of
time on these aspects as well, and not only
just looking at a candidate which shows very
good activity or which has very good inhibitory
power against an enzyme or a protein and so
on.
And of course toxicity is another big issue,
one needs to do lot of experimental studies
on fish, on animals and so on to identify
toxicity, and there are different computational
tools also which can help you to predict toxicity
of compounds, the metabolites and so on.
So in the next few weeks, we are going to
talk more about this, before we actually jump
into the predicting the activity of various
lead molecules.
So we will talk more in the next class, thank
you very much for your time.
