SeeSAR

Beginner’s Guide
Version 13 - Midas
Time to start an interactive dialog with
your compound!

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 Content

0. Before you start 3

1. Basics 10

2. Adding molecules 36

3. Docking 46

4. Covalent Docking 55

5. Inspirator 64

6. Similarity Scanner 79

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0. Before you start

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Continue with your last Find an introduction to
project. SeeSAR‘s interface.

Start your drug discovery

project here.

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SeeSAR comes with a “Color blindnes” mode.
It can be turned on in the “Appearance” menu.

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Lost your compound? Zoomed out too far?
Focus the view on the compound with the space
bar.

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Use the “L” hot key for labeling.
SeeSAR allows you to label a lot of molecules to
provide you with interesting details on
individual contributions of atoms to the overall
binding affinity, molecular torsions, and much
more.

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To save computational time and resources, it is
possible to select what parameters are
calculated once a molecule is added to one of
SeeSAR’S modes.
Got to “System” and select “Calculation”.

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In the table, select which parameters are to be
calculated for the respective modes.

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1. Basics

SeeSAR is your intuitive, visual drug design

platform. Covering every step of your drug
discovery process — from virtual screening to
fragment-based design — SeeSAR fosters ideation
in the most fun and comprehensive way.

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Start new project and clear different modes In this section you can find:
here. - Changelog for SeeSAR
This is also the location to save/load previous - Help
projects or molecules. - System settings (e.g. Calculations, licence
settings, systemlog, …)
- Appearance (layout, theme)
- Utilities (Focus view, screenshots, 3D scene
export)
- Tools for labeling and measurement
- Visualization settings

The bullhorn icon informs you if a new version

of SeeSAR is available.

A notification changelog can be found here.

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Type a pdb code in the search box and press
enter to download a protein directly from the
pdb. For this guide we will use 2ZFF as example.

Note:
You can also load your protein from a file, via
the file menu button.

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 2.

1.

The protein is loaded and all molecules, buffers,

co-factors etc will be listed.
Please (1.) select the ligand or chose to not
extract a ligand and (2.) press the “Apply”
button.

Note:
If you are not sure what name contains which
molecule, click on the name and have a look at
the 2D structure below.

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 After ligand selection, all residues within a 6.5
Angstrom radius around it are automatically
selected and presented in the model.

Click on the ligand. Its structure will be

presented in the 2D window.

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 3D-viewer:
• right-click to rotate
• mouse-wheel to zoom
• middle-click to shift

Tables:
• drag rim to re-size
• click entries to select

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Adjust background color

Change the table layout

Switch between dark and

light theme

Adjust lable size

Switch to color blindness

mode

If you want to customize the layout of SeeSAR,

click on the ‘appearance’ button in the top right
toolbar.
For this guide will use the light one, but please
feel free to use whatever you prefer!

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Note that you are in the Protein mode. The
mode switch button shows in which mode you
are and allows you to change the mode as well.
Hover over it so see your options.

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In the Proteins mode you
can load and superpose
proteins.

The Binding Site mode

sets the reference
pocket.

The Protein Editor mode

is for editing side chains,
deleting waters or
buffers, or search for
similar binding sites.

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The Analyzer mode is for
filtering molecule sets,
hit triaging etc.

The Molecule Editor

mode is for designing
new molecules in 3D.

The Inspirator mode

helps you to generate
new ideas.

In the Docking mode you

can generate poses for
new molecules.

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The Similarity Scanner is
a ligand-based mode
enabling fast and
efficient 3D alignment of
a set of input molecules
on a templace molecule.

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As the 3D view can easily get busy, let’s
customize the visualization.

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 The view controls let you toggle on/off:

Metals

Co-complexed ligands Water molecules

Individual amino acids Backbone

Complete structures Surface

Let’s hide the secondary structure, by clicking on

the “Chain-H” button in the backbone tab. Upon
clicking it turns grey (deactivated)

Note:
All buttons are clickable, so that you can hide all
parts of one protein in one click (useful with
several proteins).

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If you want to add or remove individual amino
acids after the automatic selection of residues
for the binding site, right click your ligand and
add it to Binding Site mode.

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You are now in the Binding Site mode.

Residues already included in the binding site are

highlighted in pink.

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Here you can search for unoccupied binding
pockets.

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 2.

Unoccupied pockets are listed and presented

with their respective color in 3D.

You can add or remove binding pockets and

residues in 3D with the key combination ctrl +
right left click.
To display all residues, toggle the residue
selection in the visualization bar (1.)
Confirm your selection (2.)

1.

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Go back to the Protein mode to inspect the
binding mode of the ligand inside the binding
site.

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For the next step make sure that ‘Hyde Coloring’
is turned on. You can do that in the
‘Visualization’ menu.

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The colored spheres depict the contributions of
each atom to the estimated binding affinity.
Red means unfavorable contribution, green a
favorable contribution and the bigger the
sphere is, the stronger is the effect. No sphere
means that such atom is not estimated to have
a significant impact on the binding affinity.
To find out more about each Hyde sphere
activate the label function and click on one
atom.

Note:
You can use the shortcut key ‘L’ + left click to
label your atoms.

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Check-out the other analysis options!

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‘Add to Molecule Editor’ is accessible with a
right-click on the table entry. This copies the
molecule into the mode and automatically
switches to that mode.

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 The editor-menu will appear on the top left.
There you can:

Add atoms Change Adjust Remove Store the new molecule to the table
or rings charge torsion atoms after a template-based docking

Create a new Change atom Change bond Undo/redo Store the current
molecule type type molecule to the table

To edit a molecule ALWAYS:

1. select (atoms or bonds)
2. modify (using the function of choice from above)

Note that many editor functions have shortcut-keys.

E.g. select a bond and type 1, 2 or, 3 on the keyboard,
or select an atom and type the element (C, N, O, …).

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As an exercise, we add an amino group to the
ring by selecting the Hydrogen in meta-position
and changing its element type to “N”.

Note:
During editing you see all hydrogens but no
estimated affinity and no Hyde spheres.
To see them, 1st add the edited ligand to the
table (with the green button) and 2nd select the
new entry in the table!

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If you click on the molecule entry you see the
estimated affinity and related coronas, but only
polar Hydrogens. The editor menu is locked
now.

To continue editing, click on the ‘Resume’

button in the center!

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Now let’s add a methyl group in the meta
position. Again, storing this in the table, we see a
further increased affinity estimate.

If you are running out of ideas: try the

Inspirator mode.
To get your molecule there select it with the
checkbox at the front of every row and add it to
the Inspirator mode. It will help you to replace
parts of the molecule, further grow the
molecule or merge molecules.

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2. Adding Molecules

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If you want to add your own molecules to a
SeeSAR-session: Use e.g. your favorite drawing
tool and save the molecules as sdf-, smiles-, or
mol2-file.

Switch to the Analyzer mode in SeeSAR and

add your molecules via the load button or
copy/paste them to the input library field.

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Alternatively, copy/paste (ctrl + c/ctrl + v) your
molecules (as smiles or sdf) here.
For example, copy the three molecules below,
to change their names:

O=C(N1CCCC1)c2c3c(NC=C3)ccc2
O=C(N1CCOCC1)c2c3c(NC=C3)ccc2
O=C(N1c2c(c(N)ccc2)CC1)c3c4c(NC=C4)ccc3

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Double click on the molecule name (‘no name’ in
this case) to change it. Confirm the change with
the enter key.

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To transfer all of your compounds to another
mode (e.g. to dock them in the Docking mode),
click on the ‘Checked’ column and select ‘Check
all’ to mark all molecules in the list.

If you want to transfer only some of the

molecules, check them individually in the
column.

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Click on ‘Add checked molecules to mode’ and
select the mode of your choice to work with the
molecules.
Since we want to dock them, we will select the
Docking mode.

The docking procedure is explained in Section 3

(Docking).

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You can also create new molecules in the
Molecule Editor mode.

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Let’s start with a benzene ring.

Once you clicked on ‘Benzene’ a ring will appear.

Zoom in on the ring with the space bar or via
‘Utilities’ → ‘Focus View’.

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You can modify your molecule in the 2D and 3D
window.
In 2D you can add rings and change the bond
type.
In 3D it is also possible to select the hydrogen
atoms and replace them with ‘Change element’
icon. You can also use hot keys for elements,
e.g. use ‘C’ to change an atom to a carbon or ‘N’
to change it to a nitrogen.

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Once you are finished, export the molecule to
the table with ‘Save edited molecules to table’.

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3. Docking

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The Docking mode is used to place (= dock)
molecules at the targets binding site.

You need ligands to dock them. See Section 2

(Adding Molecules) on how to add molecules to
the docking library.

Note:
ALL molecules in the ‘Docking library’ will be
docked if they are added.

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To start your docking, press the ‘Standard
docking: Generate poses’ button.

At most 10 poses per molecule are generate

this way, as we have left the docking settings on
default.

The next slide will explain how to adjust

docking parameters to refine your docking
results.

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‘Maximum Number of Poses’ defines the
highest possible number of poses that will be
generated for each molecule. SeeSAR
generates 10 poses per default.
‘Clash Tolerance’ defines how SeeSAR handles
clashes between ligand and tartget during
docking. For tight binding sites increase of the
tolerance to ‘Medium’ or ‘High’ may improve
the results.
‘Allow Ring Conformations’ can be used to
allow energetically unfavorable ring
conformations (twist, boat).

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The ‘Generated Poses’ table will be populated
with generated poses of the ligands from
‘Docking Library’.

To assess the affinity of the generated poses

check all poses with the ‘Checked’ column and
‘Check all’.

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Then go to ‘Calculations for checked molecules’
and select ‘Estimated Affinity’.

Note:
You may restrict the HYDE-calculation to a pre-
selected set of checked molecules.

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Now the estimated affinities appear as a range
on the logarithmic scale.

Clicking on a column header sorts according to

this value.

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To inspect multiple poses in comparison, toggle
the permanent visibility by marking a molecule
as reference. Now stay visible as you select
other molecules.
You can even color each molecule to
differentiate them.

You can calculate more pose assessment

parameters with a right click on a molecule, or
using the method describe in the previous slides
to calculate them for all checked molecules.

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 You can add notes and descriptors in the
molecule table window.

3D Add Molecule
visibility anotation color

Mark as Mark as
favorite active/inactive

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4. Covalent Docking

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You can perform covalent docking at any PDB
protein structure. PDB files that contain a
covalent ligand provide this information upon
loading within the info icon.

For this example, we will use the PDB 7TLL.

The linking point is represented as R in the 2D

structure.

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After defining your ligand transfer it to the
Docking Mode.

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Generate docking poses with the “Covalent
docking” button.

You can set your parameters the same as for

standard docking.

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Your results will be displayed in the “Generated
Poses” table.

If you have selected several residues as

potential targets you can switch between them
by clicking on the anchor point.

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If no covalent linking point of the structure is
defined, you can introduce it in the Protein
Editor Mode.

Select the atom of the target residue (e.g. cys,

lys, ser) which will be replaced with the ligand.

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Use the “Change element” icon and select “[R]”
or use “R” on your keyboard to introduce a
linker in that position.

Export the modified protein back to the Protein

Mode. Be sure, that your target residue is part
of the binding site.

Note:
The position of the linker atom is important for
the outcome of the docking. Please check the
elaborated and comprehensive Covalent
Docking Guide on our website for more details:

Covalent Docking Guide

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During covalent docking, your ligand is docked
in its bound state. Therefore, your structure has
to include a linking point R and take into
account any transformations that occur at the
covalent warhead.

You can introduce a linker by selecting an atom

and transform it into a linker.

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You can introduce a linker atom to your SMILES
string with [R*].

In this example we have transformed an

acrylamide warhead to its bound form to
prepare the ligand for covalent docking.

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5. Inspirator

The Inpspirator Mode supports you in the

generation of ideas how to improve your
compound. Grow your molecule into unoccupied
binding sites, explore small modifications, and
replace whole scaffolds.

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For this guide we will use PDB 2ZFF as example.

Load it in the Protein Mode and select a ligand

to work with.

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Transfer your ligand to the Inspirator Mode.

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 The Inspirator Mode features several tools and
applications to generate ideas how to improve
your compound or to find novel scaffolds.

Linking&Merging: MedChemesis:
Connects two fragments Creates a series of analogs

ReCore: FastGrow:
Replaces scaffolds Grows into binding pockets

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ReCore:
This tool screens millions of molecular
fragments to find replacements for a 3D
scaffold. To use the tool, you need to download
and add a ReCore index (= fragment library) to
SeeSAR.

ReCore indices can be accessed and

downloaded directly from SeeSAR or from our
website:

Download more libraries

Got to “System” and select “Inspirator”.

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Here you can download and add ReCore indices
to SeeSAR.
Once you are done adding your indices, confirm
everything with “Apply”. Then you can close the
window.

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 Click on bonds to set constraints (= exchange
vectors) at your molecule. You can do this in 2D
or 3D.

Subsequent click on the same bond changes

the direction of the vector (= what part should
remain and what part is to be replaced). A third
click removes the vector.

With at least two cutting points ReCore becomes

available. Push the “Core replacement” button
to generate results. You active ReCore index will
be used for this.
Saturated part of the If you want to use another one, go back to
molecule will remain “System” → “Inspirator” to change the index.

Grey-out part of the

molecule will be replaced

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Note:
It’s also possible to set more than two
constraints or to select hydrogen bonds as
vectors.

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 FastGrow:
To grow into a binding site, select a bond in 2D
or 3D to select which part of the molecule
should be kept. Only one selection is required
to perform growing.

Once you made a selection, the “Growing”

button will become active. Push it to generate
results.

Saturated part of the

molecule will remain

Grey-out part of the

molecule will be replaced

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Results will be added to the molecule table.
The grown part is highlighted, and the
respective name of the used fragment is added
to the molecule name.

Note:
It is also possible to grow from a hydrogen in 3D.

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SeeSAR comes with a growing library featuring
over 12 thousand fragments.
A larger library featuring over 120 thousand
fragments can be downloaded for free from our
website:

Download more libraries

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MedChemesis:
Once an individual molecule has been loaded
into the Inspirator Mode, “Analoging” can be
used to generate a series of molecules based on
the query compound.

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Results will be added to the molecule table.
The transformed part of the molecule will be
highlighted and the applied medicinal chemistry
transformation is added to the molecule name.

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Linking & Merging:
If you want to connect two different
fragments/molecules you need to load both of
them to the Inspirator Mode simultaneously.

To do so check both molecules and select “Add

molecules to Inspirator”.

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Set the vectors to connect both molecules. You
can also replace undesired parts in the process
leading to a fragment merging.

Once at least two vectors were set, the

“Linking&Merging” button will become active.
Press it to generate results.

Note:
Linking&Merging applies the current active
ReCore index. You can change the used
fragment set in “System” → “Inspirator”.

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6. Similarity Scanner

The Similarity Scanner is a powerful LBDD tool to

align molecules based on their molecular
features. This allows you to perform virtual
screening even without a target structure.

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 The Similarity Scanner can be used for liband-
based drug discovery.
You can add molecules as SMILES by copy-and-
paste those with [Ctrl + V] or load those via the
toolbar.

For this example, we will work with two

compounds:

O=C1Nc2ccc(Cl)cc2[C@@](C#CC2CC2)(C(F)(F)F)O1 Efavirenz
Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(N)c1Br Etravirine

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Select a ligand (in this case Efavirenz) as a
template in the molecule window. Generate
alignment poses with the play button.

You can add pharmacophore constraints and

adjust the screening parameters as well.

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Generated poses will receive an alignment score
which can be used to rank the compounds.

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 Have fun and enjoy your
interactive drug discovery
journey with SeeSAR!

If you have any problems,

please reach out to us:
support@biosolveit.de

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