ADME Profiler 2.

0 - Documentation
A brief overview:
This version of ADME Profiler was completely rewritten due to fundamental limitations of the
architecture of the original version. The focus of the original version was to allow users to generate ADME
predictions on their desktop. The intent of this version is to focus on hypothesis generation through data
exploration which I believe is the key to successful design.
The code is now entirely a product of Pharmacopeia. Every user has the right to be actively involved in
its future development: point out uses that help, point out places where it did not help, suggest new ways you
would like to explore your data or publicly available data sets, suggest new ADME/Tox endpoints you would
like to be able to explore etc..
The remainder of this document is organized into answering practical questions such as: How do I do a
substructure search? How do I export an SD file from excel? It also contains brief discussions explaining how
various things work such as: What are these eggs? How is the similarity between two molecules calculated?
Answers to the latter types of question are important because if we understand how something works we are
better able to come up with ideas from it when it fails.

How do I get started?

How do I get an SD file with my data?

What properties can I calculate?

What is a pIC50 and how do I convert my IC50s to pIC50s?

How do I make a scatter plot?

How do I get the chemistry to popup when I move the mouse over a point in a scatter plot?

How do I get the eggs?

What do the eggs mean?

How do I effectively plot biological activities of my compounds?

How do I do a substructure search?

How do I do a similarity search?

What can AP tell me about the blood brain barrier penetration potential of my compounds?

How can AP help me address a hERG liability of my series of compounds?

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How do I get started?
First, to start ADME Profiler, under “Start→Program Files” there is a menu “Pharmacopeia”. You will find
“ADME Profiler” here. Once you start ADME Profiler there are three ways to get molecules into the grid. The
first is through starting with an empty grid. You get an empty grid by going to “File→New” as shown in
Figure A. This creates a grid with a single empty cell as shown in Figure B. To start entering molecules
double click on the empty cell. This will open up the “ChemViewer”. From the “ChemViewer” you can
among other things open ChemDraw and draw or paste your structure. Follow the links to the “ChemViewer”
to see more detail as to how this works. The second way, better for bringing many molecules and their
associated data in to ADME Profiler, is through an sd file. To import an SD file go to “File→Import→SD File”
as shown in Figure C. If you want to know how to get your data into an SD file ready for ADME Profiler, go
to “How do I get an SD file with my data?”. Once the MDL databases are in full use saving an SD file will be
straight forward right from the corporate database. In the interim we have created a third way to bring in
project datasets. As shown in Figure D selecting “File→PCOP Projects” will open, as in Figure E, a set of
literature data sets and a list of current projects at Pharmacopeia. While the full list of projects appears for
everyone you will only be able to access the data for projects for which you have access to the corresponding
folder on the W drive. If you are not on the PCOP network you will not be able to access any of the project
data. The data will not be entirely up to date but should be updated once or twice a month. Additional data for
any of these projects can be added very easily, just ask. Also, new projects can be added to the list easily as
well. The literature data sets are part of the installation and can be accessed anywhere.

A B

D
E

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What is an SD file and how do I get one?
For now the most common way to get an SD file is use one of the project team spreadsheets in Accord for excel
and export from there.
Step 1: Accord is very finicky when saving to an SD file so you might have to do some reformatting.
• The molecules should be in the first column.
• The column header for the first column must be “CHEMISTRY” all in caps and the cursor must be in
this cell.
• You should have only 1 row for column headers. So the second, third, etc. rows should all be molecules
and their associated data.
Step 2: As shown in Figure A below, under the “Chemistry Menu”, choose “File”, and then choose “Export
Table”.
Step 3: This should bring up an file browser with the title “Export table”. As shown in Figure B below first
change the file format to “MDL SD Molfile”. As a warning there are a number of MDL formats possible.
Make sure to pick the “MDL SD Molfile”.
Step 4: Hit the browse button and save the file to wherever you like with whatever name you like. For
example, you could go to your desktop and save the file as “KinaseSAR.sdf”

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IC50 versus pIC50 – Everything you’ve ever wanted to know.
Everybody knows what an IC50 is but what is a pIC50. Mathematically, pIC50 is just minus the logarithm
(base 10) of the IC50 (from Molar units). So an IC50 of 1 nM (i.e., 10-9 M) is equivalent to a pIC50 of 9, an
IC50 of 10 nM (i.e., 10-8 M) is equivalent to a pIC50 of 8, an IC50 of 100 nM (i.e., 10-7 M) is equivalent to a
pIC50 of 7, and an IC50 of 1 µM (i.e. 10-6 M) is equivalent to a pIC50 of 6. Every factor of 10 increase in
potency leads to an increase of 1 in the pIC50. Similarly every decrease in potency by a factor of 10 leads to a
decrease of 1 in the pIC50. Mostly, we report IC50s. In ADME Profiler, has a simple way to convert a column
of IC50s to pIC50s. First select a cell in the column you wish to convert and then assuming the units for your
IC50 are nM choose “Compute→Basic Math→pIC50 (nM)” as in Figure A. If the units of the column are µM
choose “Compute→Basic Math→pIC50 (µM)”. Rather than overwriting your IC50 column, this will create a
new column at the end of the grid. Figure B shows the two columns that are create after the IC50s for FGFR1
and PDGFr are converted to pIC50s.

A B

Whenever you plot a biological activity you should use pIC50 not IC50. The case for this is best made with an
example. Figure C shows the two activities (PDGFRb vs. FGFR1) plotted as IC50s. There is no information
in Figure C because most of the action is in the lower left corner (the most potent molecules). Figure D shows
the same two activities plotted as pIC50s. In Figure D it is evident that the points are spread more evenly
through out the figure. The entire discussion above is exactly the same if IC50 is replaced by Ki, Kd, EC50,
etc.. Anytime concentrations are used they should be converted to minus log concentrations.

C D

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Scatter Plots:
To scatter plot is the primary way to explore ones data. To get a scatter plot first you must go to grid from
which you want to make a scatter plot. Then, as in Figure A, select “Charts→Scatter Plot”. From here you can
navigate to many views of your data. Figure B below shows the options for investigating your data:
• The properties used for the x-axis and y-axis can be dynamically changed using the drop down menus in
the lower right and upper left corners respectively.
• The chemistry pop up can be turned on by selecting the check box in the upper right corner labeled
“Show Structure”. When this box is checked, the structure will pop up when your mouse goes over a
point.
• The absorption egg can be turned on by selecting the check box in the upper right corner labeled “Well
Absorbed Drug Space”. The egg can be drawn for any two calculated properties.
• The CNS penetration egg can be turned on by selecting the check box above the chart labeled “CNS
Penetration”.

Turn on the
Change the absorption
y-axis egg

Modify the Turn on the

chart pop-up
properties chemistry
such as
size the Turn on the
dots by CNS egg
other
properties
Change the
B x-axis

5
What do the eggs mean?
In the upper right corner of a scatter plot (see Figures A and B below), there are 2 check boxes labeled
“CNS Penetration” and “Well Absorbed Drug Space”. These cause ellipses (eggs) to be plotted that represent
in some sense the space of highly CNS penetrent compounds and well absorbed drugs. Most every one is
familiar with the rules of five such as molecular weight < 500. This does not mean that all orally absorbed
drugs have a molecular weight below 500. The number of 500 was chosen because 95% of orally absorbed
drugs have a molecular weight below 500. The eggs should be thought of a 2-dimensional “Lipinski criteria”.
For example for the well absorbed drug space, the inner ellipse indicates the smallest ellipse that contains 95%
of known well absorbed drugs and the outer ellipse is the smallest ellipse that contains 99% of known well
absorbed drugs. The ellipses say nothing about the percentage of molecules inside that are well absorbed only
that the percentage of well absorbed drugs is significantly higher inside the eggs than it is outside the eggs. It is
also important to keep in mind what “Well Absorbed” means. For this a drug was considered “Well Absorbed”
if its human intestinal absorption was at least 90%. In the same way the inner CNS ellipse is the smallest ellipse
that contains 95% of highly CNS penetrant molecules and the outer ellipse is the smallest ellipse that contains
99% of highly CNS penetrant molecules. Here highly a molecule is considered “Highly CNS Penetrant” if its
equilibrium concentration in the brain is at least as high as its concentration in the blood (logBbR > 0.0).
The last point worth noting is that eggs for these two properties can be shown for any of the properties
calculated in ADME profiler – not just AlogP98 and FPSA. Looking at the eggs in alternate property spaces
might give insight to the problem that is missing in the classic AlogP98 vs. FPSA plots.

Well Absorbed
drug space

Highly CNS
penetrant
space
B

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What properties can ADME Profiler calculated?

All the properties that can be calculated can be found under the “Compute” menu shown in Figure A below.
Selecting the “Compute→Properties” will compute
• FPSA
• AlogP98
• Molecular Weight
• Rotatable Bonds
• Hbond Acceptors
• Hbond Donors
• Lipinski Violations
• FabsLevel
• logBbR
• HERG (hERGpIC50)
• Human Intestinal Permeability (Absorption_Probability)
• Blood Brain Barrier Permeability (BBB_Probability)

Beyond the standard properties there is a model for hERG inhibition, and more advanced models for human
intestinal absorption, and blood brain barrier penetration. Each time one of the options is selected, new columns
will be added with the corresponding properties – as in Figure B.

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Properties:

FPSA - Polar Surface Area (the F is for fast in case your wondering)
The polar surface area of a molecule is the surface area of the polar atoms (oxygen, nitrogen and hydrogens
bonded to oxygen and nitrogens) of the molecule. To calculate the surface area of an atom within a molecule
imagine each atom as a ball with a radius equivalent to its Van der Waals radius (~1.9 Å for carbon, 1.7 Å for
nitrogen, 1.5 Å for oxygen etc..). The amount of surface area for an atom then is just the amount of the surface
of the atoms sphere that can be seen from the outside. One caveat with PSA is that everyone uses slightly
different Van der Waals radiis. This has the effect that while tow PSA calculators will give numbers that
correlate nearly perfectly they will typically differ by a scale factor. So you cannot always take someones
conclusion about PSA cutoffs for example as absolute to every PSA calculator. An example of the polar
surface area of a molecule is shown below going from the standard 2D depiction (Figure A), to a 3D
conformation (Figure B) finally to the polar surface area which is the exposed surface in Figure C colored Blue
(nitrogen), red (oxygen) or white (polar hydrogens).

OH A B
N
N O
N
O H

FabsLevel – Absorption classification

This should take the values 0, 1, 2, or 3. It refers specifically to the location of the molecule in the FPSA vs.
AlogP98 absorption egg. 0 means that the molecule is in the inner egg. 1 means that the molecule is in the
shell between the two eggs. 2 means the molecule is outside the outer egg. 3 means the molecule is way
outside the outer egg.

logBbR – Prediction for a molecules propensity to penetrate the blood brain barrier.
lobBbR = log of the ratio of the concentration of the molecule in the brain to that in the blood. A value of 1
means the molecule is predicted to have a 10 times higher concentration in the brain than in the blood. A value
of 0 means the molecule is predicted to partition equally between the blood and brain. This is a model
originally implement from the literature by Bill Egan. It uses only AlogP98 and FPSA to make its assessment.
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BBB_Probability – This should be interpreted as the probability a given compound will have a brain
concentration to blood concentration of at least 0.1 (logBBR = -1). A numbers greater than 0.5 indicate
compounds that have a good chance of being brain penetrant while numbers below 0.5 indicate compounds
having a low chance of being brain penetrant. The model takes into account a wider range of physical
properties than does the logBbR model. It includes FPSA, AlogP98, number of rotatable bonds, molecular
weight and number of hydrogen bond donors and acceptors. So far it has done better than the simpler logBbR
model.

Absorption_Probability-The probability a molecule will be greater than 90% absorbed

This will be a number between 0 and 1 indicating the likelihood that the given molecule will be passively
absorbed. It is somewhat more complicated than the usual egg models. It uses FPSA, AlogP98 and a second
measure of polarity called the hydrophilic index.

hERGpIC50 – This is a calculated pIC50 for hERG inhibition.

This is a complex model that depends on the structure, i.e., distance between atoms is taken into account. More
detailed information regarding this models calculations can be obtained by right clicking on the molecule of
interest and selecting HERG Depiction.

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The ChemViewer

The ChemViewer can be accessed in one of two ways. The simplest way is to simply double click on the
chemistry cell of interest. This will open the ChemViewer with the molecule in the selected cell. The second
way, depicted in Figure A below, is to select a chemistry cell, right click, and select the “Edit Molecule” option
in the menu that appears. The purpose of the buttons in the ChemViewer is shown in Figure B below. You can
open ChemDraw and edit the structure. If it is a structure of interest it can be added to the grid either by
replacing the original molecule (“Update” button) or by adding a new row (“Add to Grid” button). The
ChemViewer will allow you to do a substructure or similarity search. A substructure search will add a new
column at the end of the grid which contains the number of times the substructure occurs in the corresponding
molecule of that row. The similarity search will add a new column with a number between 0 and 1 that
indicates the similarity between the molecule in the ChemViewer and the molecule in the corresponding row.
The “Align” button allows you to realign every molecule in the grid that has the substructure in the
ChemViewer.

Put this molecule in

the grid in a new row
Orient every molecule
with this substructure
so the substructure is
aligned this way

Perform a substructure
search with this structure

Perform a similarity
search with this structure

Rename this molecule

Open Replace the molecule in the

ChemDraw current cell with this molecule

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Eliminating hERG activity

There are two ways to access information of hERG. The first is simply to use the hERG model to generated a
calculated hERG pIC50. To do this make sure the grid of interest is the active window and select
“Compute→HERG” (Figure A below). This will add a new column at the end of the grid labeled
“hERGpIC50” (Figure B below). The second way ADME Profiler helps with addressing a hERG liability

A B

within a chemical series is through more detailed analysis of a single molecule. This is done through what we
call the model viewer. To get the viewer, scroll through the grid to the compound of interest. Select the
compound of interest and right click which will bring up a menu. Select the “HERG Depiction” option (see
Figure C below). This will open the “HERG Viewer” as shown in Figure D below. The model we use has the
advantage that it calculates a contribution from each atom to the overall activity. The hERG viewer simply
shows this information. The circles are atoms calculated to increase the hERG activity and the squares are
atoms calculated to decrease the hERG activity. So we would like to see few large circles and many large
squares. The color is simply the atom type, grey – carbon, blue – nitrogen, red – oxygen etc.. The colors are
shaded to indicate hybridization – light Sp3 atoms and dark Sp2 atoms. The large light blue circle is the basic
tertiary amine while the dark gray circles on the left are the aromatic carbons of the benzoxazole. This meant as
an interactive tool. From the viewer you can open ChemDraw and change the structure. If you like the
corresponding changes in the viewer you can then add the newly designed molecule to the grid.

D
The calculated
hERG IC50 for
the current
molecule
C The selected
atom’s
contribution to
the calculated
Open the Rename the Add the hERG activity
ChemViewer molecule prior current in log units
to edit the to adding it to molecule to
structure the grid the grid

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Tools for improving CNS penetration
There are two models for CNS penetration available in ADME Profiler: “LogBbR” and “BBB_Probability”.
The first is calculated under the “Compute→Properties”, and the second is calculated by choosing
“Compute→Blood Brain Barrier”. As with most aspects of ADME profiler with these models comes a good
way to visualize them for the purpose of understanding what they are telling you. For this example I used the
PDR data set which can be found under “File→PCOP Projects” and selecting “Literature-PDR”. To get this
picture first compute “Properties” and “BBB Probability” and then select “Charts→Scatter Plot”. This should
create a scatter plot. Select the check boxes in the upper right corner for “CNS Penetration” and “Well
Absorbed Drug Space”. This will turn on the eggs and should give you a picture like the one Figure A. In the
upper left corner of the chart is a button labeled “Modify Chart”. Hit this button and select the “Link to Other
Properties” tab, as in Figure B. Under “Size By” choose “BBB_Probability” and change the size of the dots to
range from 1 to 5 pts again as shown in Figure B. You will notice that some of the molecules in or near the
CNS egg are very small indicating that the second model thinks that they will not be highly CNS penetrant.
Here I’ve selected a point (in red in Figure D) near the center of the egg but nonetheless predicted to have a low
probability of CNS penetration. By turning on the “Show Structure” check box and moving the mouse over this
point we see the molecule in Propafenone, Figure D. The eggs work as long as the two properties used in
charting are calculated by ADME Profiler. In Figure E I’ve changed the Y-axis to “Rotlbonds”. In this egg
propafenone is no longer in inner egg suggesting that given its other properties its number of rotatable bonds is
too high. The hypothesis is that to improve the CNS penetration of this compound we would want to make it
more rigid.

A C
B

D E

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Literature Data Sets

These data sets are included both for the purposes of demonstration but also to encourage exploration into the
various properties such as “Does a certain substructure have a tendency to increase or decrease CNS penetration
or Protein Binding?”

PDR – This contains all the orally delivered drugs from the PDR as of around 2000.

Absorption Data Set – This contains a number of molecules taken from the literature with measured oral
bioavailability or oral absorption value. The number in the “Human Oral Absorption” column is the
%absorbed.

CNS Penetration Data Set – This contains a number of molecules taken from the literature with measured
ratios of brain concentration to blood concentration. The number in the “logBB” column is the log of the ratio
of the concentration in the brain to the concentration in the blood.

Protein Binding Data Set – This contains molecules from the literature with measured protein binding. The
number in the “%PB “ column is the percent protein bound for the given molecule.

hERG Data Set – This contains a number of molecules taken from the literature with measured hERG IC50s in
a variety of patch clamp assays. The number in the “pIC50” column is the measure hERG pIC50 from the
literature.

Kinase Example – This is a dataset of molecules taken from the literature with data for PDGFr and/or FGFr.
This data set is meant to be used for instructional purposes.

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