Introduction to Hypotheses and Constraints

Introduction to hypotheses

A Catalyst hypothesis enables you to search a database to see if it has any compounds that contain a particular set of topological or geometric features or to see how well a compound fits a model for the important characteristics of a class of drugs.

What is a hypothesis in Catalyst?

A hypothesis is a specification of the distinguishing physical and chemical characteristics of a class of molecules, where the description of the key features can range from very general to very precise.

A hypothesis can be created by constructing it in the View Hypothesis workbench or by automatically generating it from a training set of compounds with the Generate Hypothesis workbench.

How can you use a hypothesis?

There are many types of tasks you can do with a hypothesis:

Search a database for compounds that match the hypothesis.
Estimate the activity of a compound.
Use Compare/Fit to fit a particular conformer of a molecule to a hypothesis.
Use Compare/Fit to find the conformer of a molecule that best fits a hypothesis.
Use Compare/Fit to match the structure and features of two hypotheses.
Use Score Hypothesis to assess how well the hypothesis fits a training set of molecules and to estimate their activities.
Use Regress Hypothesis to obtain a linear regression of the ability of the hypothesis to predict activity for a training set of molecules.

What kinds of features can a hypothesis have?

A hypothesis can contain any combination of the following feature specifications:

Chemical functions. The following functions are predefined in the Catalyst Feature Dictionary. You can create additional functions and add them to the list.
Hydrogen-bond acceptor
Hydrogen-bond acceptor (lipid)
Hydrogen-bond donor
Hydrophobic
Hydrophobic aliphatic
Hydrophobic aromatic
Negative charge
Negative ionizable
Positive charge
Positive ionizable
Positive ionizable-1
Ring aromatic
For a description of each function, please see Description of Catalyst's predefined chemical functions.
Particular atoms or fragments. For example, a carboxylate or thiol.
Atoms belonging to a specified set. For example, an atom can belong to a set of possible elements, such as oxygen, nitrogen, sulfur.
Atom characteristics. For example, specify that atom must have a valence of 3 or 4 and a charge between -1 and +1.
Bond type. For example, a bond could be single, double, or triple and either endocyclic or exocyclic.
Location constraints. For example, specify the spherical boundary for the location of an atom or feature.
Distance constraints. Determine the minimum and maximum distances between objects. For example, specify that a hydrogen-bond donor be 15-20 Å from a halogen atom.
Angle or torsion-angle constraints. For example, define an angle limitation between three molecules or an angle of rotation around a bond.
Excluded volume. Define a spherical volume within which nothing is allowed.
1D (scalar) values. For example, define an allowable range for the molecular weight of a molecule.
Geometric objects. Geometric objects such as centroids, vectors, projected donor and acceptor points, and best-fit planes can be defined and used for specifying constraints.

For illustrated examples of hypotheses, see Examples of hypotheses.

How do you create a hypothesis?

Catalyst provides several ways of creating a hypothesis:

Constructing. You can interactively build a hypothesis in the View Hypothesis workbench.
You can construct a hypothesis when you already know the basic structure you are interested in -- for example, if your hypothesis is based on the structure and/or topology of a particular molecule or class of molecules, you can use it as a template for building the hypothesis.
Generating. With a set of appropriate lead molecules for which you have activity data, you can use Catalyst to automatically generate a hypothesis in the Generate Hypothesis workbench. You would do this when you want to find out what common arrangement of functions might explain the activities of your training set. You enter the compounds and their measured activities into the Generate Hypothesis workbench spreadsheet. Catalyst evaluates the structures and activities of the compounds and generates a set of hypotheses with geometric arrangements of functions that "explain" the activities of the training set.
Importing. You can import a hypothesis that has been saved in a Catalyst CHM file or an MDL MOL file.

Further information on creating a hypothesis in the workbenches:

How to use the View Hypothesis workbench to build a hypothesis.
How to use the Generate Hypothesis workbench to request Catalyst to generate a hypothesis for you.
How to import objects to load in a previously saved hypothesis.

Introduction to location constraints

Any feature in a hypothesis (either a function or chemical fragment) can have a location constraint, which is a sphere that defines how close a component must be to the feature to be considered a "match" during Compare/Fit, Score,, and Regress operations and database searches.

More information on why you would want to create a hypothesis with location constraints and how to do it:

What are location constraints?
Why and when are location constraints important?
Building hypotheses that have location constraints
To add location constraints to functions and atoms
To change constraint values and names

What are location constraints?

Location constraints define the target location and the geometric tolerance on the location for atoms or functions in a hypothesis. You can specify location constraints for any feature or function in a hypothesis. The location constraint defines the volume in which the function or fragment can reside.

A location constraint appears as a sphere surrounding the item to which it is attached. The picture below shows location constraints displayed in mesh, transparent, and solid styles. The center of the sphere defines the ideal or target location

A hypothesis should contain at least three location constraints for the location constraints to be meaningful (four if chirality specifications are involved), since they describe the relative locations of functions and atoms within a molecule.

Why and when are location constraints important?

Catalyst uses location constraints during database searches, during Compare/Fit, Estimate Activity, Score, and in Regress Hypothesis.

Database searches

For the geometric characteristics of a feature in a hypothesis to be considered during a database search, the feature must have a distance or location constraint. If a feature has a weight but no location constraint, the feature is merely checked to see if it is present and matches other characteristics of the feature in the molecule, but its location is ignored. For more precise details, see What determines if a compound matches a hypothesis.

Compare/Fit operations

Hypothesis features without location constraints have the same effect in Compare/Fit as in database searches. Other characteristics of a feature are checked for a match, but without a location constraint, the 3D location of a feature is ignored.

Building hypotheses that have location constraints

When you add a location constraint to a function or atom specification in a hypothesis, Catalyst places the center of the sphere at the location of the feature in the 3D workspace. When you create a location constraint, you use the location of an existing atom as the coordinates of the center of the location constraint, and you specify the radius of the sphere within which it may be found. You can also specify the location of the center of the sphere directly, if you know the exact coordinates.

Each atom in a molecule is located at a fixed position within the framework of the molecule. If you convert a molecule to a hypothesis, the hypothesis retains all the geometric information about the atoms in the molecule. When you add location constraints to atom specifications in the hypothesis, they are positioned within the same relative framework and hence represent the relative positions of the atoms to each other in the original molecule.

If you want to build a hypothesis that contains specific features with location constraints, you can do it in two ways using an appropriate molecule:

Use the molecule as a template to position functions with the Show Function Mapping menu item, Add the desired functions, define location constraints, and then Merge the functions.
Convert the molecule to a hypothesis with the toolbox tool and then use the atom and bond specification editors. You can then add a location constraint for one or more features at the positions of the functions or atoms.

For more information on how to add location constraints to atoms and functions in hypotheses, please see To add location constraints to functions and atoms.

To add location constraints to functions and atoms

If you want to add location constraints to atom specifications in a hypothesis, you should build the hypothesis by converting a molecule to a hypothesis, as described under To add items from the dictionary.

If you want to add location constraints to functions in a hypothesis, you should use a template molecule to build the hypothesis, as described under Using a template molecule to place functions in a hypothesis.

To add a location constraint to an atom or function, do the following in the View Hypothesis workbench:

Select the function or atom to which to attach a location constraint.
Select the Constraints/Define Constraint menu item, then select Location from the popup. Or click the Set Constraint Tolerance tool in the toolbox.
A control panel appears, as well as a mesh-style sphere centered on the selected atom or function. The color of the location constraint depends on the type of feature to which it is applied, as shown in the illustration:

You can change the style of the location constraint to solid, transparent, or dots with the global preference settings for 3D constraint style in the Global Preferences control panel (which is opened from the Preferences menu of the Stockroom and labs).
You also can change the display color using the 3D Constraint color settings.
The Name box shows the default name of the location constraint. You may change it if you want.
The Target Size box shows the default radius of the sphere. Change it if you want.
If you want to modify the position of the sphere -- for example, move it a certain distance in the x, y, or z direction -- you can do that by changing the default values (which represent the selected object's current location) in the X, Y, Z text boxes.
Select Apply to implement the change while leaving the control panel on the screen or select OK to implement the change and close the control panel. Select Reset to reset the control panel values to what they were when the control panel was opened or when you last applied values.

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