两种药效团模型搭建

How to set up a 3D QSAR Pharmacophore Generation runThe 3D QSAR Pharmacophore Generation protocol generates SAR hypothesis models (pharmacophores) from a set of ligands for which activity values on a given biological target have been measured.Note.To ensure proper exploration of the ligand conformational and pharmacophoric space, it is recommended that you run the Diverse Conformation Generation protocol prior to running this protocol.The input ligands need the following molecular properties: Activ(representing the ligand's tested activity) and Uncert(set to 3.0by default, representing the ratio range of uncertainty in the activity value). Molecular properties can be added using the Add Attribute dialog.To set up a 3D QSAR Pharmacophore Generation protocol:1.Load the Pharmacophore | 3D QSAR Pharmacophore Generation protocol from theProtocols Explorer. The parameters display in the Parameters Explorer.2.On the Parameters Explorer, click in a cell for the Input Ligands parameterand click the button to specify the ligand source on the Specify Ligandsdialog. On the dialog, select all ligands from a Table Browser, a 3D Window, or a file. The molecular properties Activ and Uncert should be set for these molecules. If they are not set, they will be assigned a default value of 0.0 and 3.0, respectively.3.Specify the pharmacophore features using the Features parameter. Selectingthis parameter opens the Select Features dialog . On the dialog, you may select the desired pharmacophore features and the minimum and maximum values desired for the final pharmacophores.4.Set the remaining parameters as desired. Parameters presented in red arerequired.Note.If using the Maximum Excluded Volumes parameter in this protocol, we recommend using a value of 5.Note. When generating SAR pharmacophores, which include excluded volumes, the algorithm looks for differences in the steric bulk between the most active compound, and the inactive compounds. However, it is possible to explicitly specify which compounds to use for this analysis. This is done by adding a Principal property to the input ligands. For normal SAR hypothesis model generation, this property is ignored. When using the HypoRefine algorithm to add excluded volumes, however, these values can be used to determine which molecules are used when placing the excluded volumes. Values that are provided will be used as follows:0,NULL: Ignore compound in excluded volume addition1 : Treat compound as Inactive.2: Treat compound as Active.How to set up a Build 3D Database runThe Build 3D Database protocol builds a Catalyst 3D conformation database. It is recommended that no more than 50,000 molecules be used as input. Use the command line program, catDB, to build larger databases. Refer toInstall_Directory/share/Catalyst/conf/catDB.doc document for more information. To set up a Build 3D Database run1.Load the Pharmacophore | Feature Mapping protocol from the Protocols Explorer.The parameters display in the Parameters Explorer.2.On the Parameters Explorer, click in a cell for the Input Ligands parameterand click the button to specify the ligand source on the Specify Ligandsdialog. On the dialog, select all ligands from a Table Browser, a 3D Window, or a file.3.Specify the database name using the Database Name parameter.4.Set the remaining parameters as desired. Parameters presented in red arerequired.How to set up a Common Feature Pharmacophore Generation runThe Common Feature Pharmacophore Generation protocol generates pharmacophores that are common to a set of active ligands. Optionally, it will add excluded volumes to the pharmacophores based on information from a set of inactives.Note.To ensure proper exploration of the ligand conformational and pharmacophoric space, it is recommended that you run the Diverse Conformation Generation protocol prior to running this protocol.To set up a Common Feature Pharmacophore Generation protocol:1.Load the Pharmacophore | Common Feature Pharmacophore Generation protocolfrom the Protocols Explorer. The parameters display in the ParametersExplorer.2.On the Parameters Explorer, click in a cell for the Input Ligands parameterand click the button to specify the ligand source on the Specify Ligandsdialog. On the dialog, select all ligands from a Table Browser, a 3D Window, or a file.3.In the Data Table, add the molecular property Principal to the molecules toset a value to make it active (2), moderately active (1), or inactive (0).You can also add the molecular property MaxOmitFeat to indicate how manyfeatures are allowed to miss for each molecule. If no values are set for these properties, the default value for all molecules for Principal is 2 and for MaxOmitFeat is 04.Specify the pharmacophore features using the Features parameter. Selectingthis parameter opens the Select Features dialog. On the dialog, you may select the desired pharmacophore features and the minimum and maximum values desired for the final pharmacophores.5.Set the remaining parameters as desired. Parameters presented in red arerequired.To set up a Common Feature Pharmacophore Generation protocol with the inclusion of excluded volumes:1.Repeat steps 1-4 from above.2.Specify the maximum number of excluded volumes to be added to a pharmacophoreusing the Maximum Excluded Volumes parameter.Note.The Input Ligands must also include a set of inactive molecules when attempting to add excluded volumes. Set the Principal value to 0for all the inactive molecules. If the Principal property is not set, all ligands are automatically assigned a Principal value of 2 (active).Note. The MaxOmitFeat molecular property also serves a purpose for inactive molecules when identifying candidate excluded volume locations. A value of 1means that all mappings where either all n or a subset of n-1features map will be considered. For more complicated data sets, it may be better to set MaxOmitFeat to 0 for the inactive molecules to avoid placing too many excluded volumes.Note.If using the Maximum Excluded Volumes parameter in this protocol, we recommend using a value of 100.Note.If the ligand source is a Graphics View of molecules that contain conformations (e.g., created by importing .cpd files), only a single conformation is employed in the protocol for each molecule. If you intend to use all conformations, you should convert .cpd files to the MDL SD file format before importing them into Discovery Studio.How to set up a Convert Interactions to Features runTo run a Convert Interactions to Features protocol1.Load the Pharmacophore | Convert Interactions to Features Generationprotocol from the Protocols Explorer. The parameters display in theParameters Explorer.2.Set the Input Interactions File parameter by navigating to a stored Ludiinteractions file. This should either be in .pdb or .msi format.3.Set the remaining parameters as desired. Parameters presented in red arerequired.How to set up a Diverse Conformation Generation runThe Diverse Conformation Generation protocol generates conformations for a set of input ligands. This protocol is often used as a precursor to other pharmacophore protocols, such as Pharmacophore | 3D QSAR Pharmacophore Generation and Pharmacophore | Common Feature Pharmacophore Generation.Note.Molecular properties are retained when using this protocol. It is often easier to set the molecular properties needed for Pharmacophore | 3D QSAR Pharmacophore Generation and Pharmacophore | Common Feature Pharmacophore Generation before running the Pharmacophore | Diverse Conformation Generation protocol.To set up a Diverse Conformation Generation protocol run:1.Load the Pharmacophore | Diverse Conformation Generation protocol from theProtocols Explorer. The parameters display in the Parameters Explorer.2.On the Parameters Explorer, click in a cell for the Input Ligands parameterand click the button to specify the ligand source on the Specify Ligandsdialog. On the dialog, select all ligands from Table Browser, a 3D Window, or a file.3.Set the remaining parameters as desired. Parameters presented in red arerequired.How to set up a Feature Mapping runThe Feature Mapping protocol generates all possible pharmacophore features for the given input ligands.To set up a Feature Mapping protocol run:1.Load the Pharmacophore | Feature Mapping protocol from the Protocols Explorer.The parameters display in the Parameters Explorer.2.On the Parameters Explorer, click in a cell for the Input Ligands parameterand click the button to specify the ligand source on the Specify Ligandsdialog. On the dialog, select all ligands from a Table Browser, a 3D Window, or a file.3.Specify the pharmacophore features by selecting the Features parameter. How to set up an Interaction Generation runTo run an Interaction Generation protocol1.Load the Pharmacophore | Interaction Generation protocol from the ProtocolsExplorer. The parameters display in the Parameters Explorer.2.Ensure that the structure you want to define as the receptor is open in a3D Window. Use the Binding Site tool panel to define the structure as the receptor.3.Set the Input Site Sphere parameter to define the active site. This can bedone in different ways:o Locate the binding sites using the Binding Site tool, select a site, and define the Input Site Sphere parameter based on the selected site.o If you have a receptor-ligand complex, the ligand can be selected to define the the Input Site Sphere parameter.o If you have some knowledge of the active site, select the atoms around the active site and use this to define the the Input Site Sphereparameter.4.The radius of the site sphere can be changed by selecting the sphere andchanging the radius in the Attributes dialog. Alternately, you can use the Data Table View to change the radius of the sphere.5.Select the receptor structure from the Input Receptor parameter list.6.Select the sphere as the Input Site Sphere parameter.7.Set the remaining parameters as desired. Parameters presented in red arerequired.How to set up a Ligand Pharmacophore Mapping runThe Ligand Pharmacophore Mapping protocol compares a set of ligands to a pharmacophore. The relevant ligand-pharmacophore mappings are exported aligned to the pharmacophore.Note.To ensure proper exploration of the ligand conformational and pharmacophoric space, it is recommended that you run the Diverse Conformation Generation protocol prior to running this protocol.To set up a Ligand Pharmacophore Mapping protocol1.Load the Pharmacophore | Ligand Pharmacophore Mapping protocol from theProtocols Explorer. The parameters display in the Parameters Explorer.2.On the Parameters Explorer, click in a cell for the Input Ligands parameterand click the button to specify the ligand source on the Specify Ligandsdialog. On the dialog, you may select all ligands from a Table Browser, a 3D Window, or a file.3.On the Parameters Explorer, click in a cell for the Input Pharmacophoreparameter and click the button to specify the input source on the SpecifyQuery dialog. On the dialog, you may select the pharmacophore from a 3D Window or a file.4.Set the remaining parameters as desired. Parameters presented in red arerequired.How to set up a Pharmacophore Comparison runThe Pharmacophore Comparison protocol aligns an input pharmacophore to a reference pharmacophore and exports it using the aligned coordinates.To set up a Pharmacophore Comparison protocol1.Load the Pharmacophore | Pharmacophore Comparison protocol from theProtocols Explorer. The parameters display in the Parameters Explorer.2.On the Parameters Explorer, click in a cell for the Input Pharmacophoreparameter and click the button to specify the input source on the SpecifyQuery dialog. On the dialog, you may select the pharmacophore from a 3D Windowor a file.e the same dialog to designate the Input Reference Pharmacophore parameter.4.Set the remaining parameters as desired. Parameters presented in red arerequired.How to use the Pharmacophore toolsThe Pharmacophore tool panel provides a quick way to selectively display, cluster, and edit a set of pharmacophore query features.To display the Pharmacophore tool panelChoose the View | Tool Panels | Pharmacophore command from the menu bar.Select FeatureChoose a feature from the menu. This becomes the current feature. The Pharmacophore tool works on one feature at a time.Note. The All Features command is an exception. This is provided as a convenience to help toggle the visibility of all features together.Show/HideCurrent Feature: Toggles the display of the chosen current feature.Location Spheres:Toggles the display of the location spheres on the chosen current feature.All Non-Features: Toggles the display of all non-feature objects.ClusterCluster Current Feature:Performs a hierarchical clustering of the current feature. Click this button to open a Dendrogram Window. By moving the slider in the DendrogramWindow, the cluster centers of the feature groups are highlighted in the 3D Window. The number of cluster centers is displayed in the status text.If no members of the current feature are selected, clustering is performed using all the members of the current feature.If a portion of members of the current feature is selected, clustering is performed only using the selected members.Note.No Dendrogram is calculated if there are less than two members of the current feature.Show Only Cluster Centers:Displays only the cluster centers of the current feature corresponding to the position of the slider in the Dendrogram Window. The Dendrogram Window must be your active window for this button to be enabled. Change the position of the slider and click the button to display other centers.Keep Only Cluster Centers: Deletes all the cluster non-centers of the current feature corresponding to the position of the slider in the Dendrogram Window. The Dendrogram Window must be your active window for this button to be enabled. To undo your changes, click the Undo button on the Standard toolbar.EditKeep Only Current Feature Selections:Allows you to keep manually selected members of the current feature. The 3D Window must be your active window for this button to be enabled.You can also use this command in conjunction with the cluster centers described in the clustering section. To include other members of the current feature in addition to the cluster centers, select the tab of the 3D Window, press SHIFT and select the additional members, and click this command. This action retains the cluster centers corresponding to the position of the slider in the Dendrogram Window, as well as the manually selected members of the current feature.Merge Hypotheses:Allows you to perform a simple merge of 2 or more hypotheses into a single hypothesis.How to set up a Search 3D Database runThe Search 3D Database protocol searches a database using an input pharmacophore. The pharmacophore can contain pharmacophore features, shapes, excluded volumes, etc. If no input pharmacophore is provided, a browse of the database is performed.To set up a Search 3D Database protocol1.Specify the database to use by selecting one from the dropdown list from theInput Database parameter. Refer to the Using the Catalyst Database Help topic for details about installing a database.2.On the Parameters Explorer, click in a cell for the Input Pharmacophoreparameter and click the button to specify the input source on the SpecifyQuery dialog. On the dialog, select the pharmacophore from a 3D Window ora file. If no input pharmacophore is provided, a browse of the database isperformed.3.Set the remaining parameters as desired. Parameters presented in red arerequired.How to set up a Search by Shape runThe Search by Shape protocol converts an input conformation of a molecule to a shape and uses it to perform a shape similarity search on an input database.To set up a Search by Shape protocol1.Load the Pharmacophore | Search by Shape protocol from the Protocols Explorer.The parameters display in the Parameters Explorer.2.On the Parameters Explorer, click in a cell for the Input Ligands parameterand click the button to specify the ligand source on the Specify Ligandsdialog. On the dialog, select all ligands from a Table Browser, a 3D Window, or a file.Note.Multiple molecules can also be used as input; however, in this case, a single shape is created using the first conformer of the first molecule. The remaining conformers and molecules are ignored.4.On the Parameters Explorer, specify the database to use by selecting one fromthe dropdown list from the Input Database parameter. Refer to the Using the Catalyst Database Help topic for details about installing a database.5.Set the remaining parameters as desired. Parameters presented in red arerequiredHow to set up a Screen Library runThe Screen Library protocol enumerates several possible pharmacophores from an input set of pharmacophore features and screens an input set of ligands using the enumerated pharmacophores.Note.To ensure proper exploration of the ligand conformational and pharmacophoric space, it is recommended that you run the Diverse Conformation Generation protocol prior to running this protocol.Note. The pharmacophores are enumerated internally within the server and not exported to disk. Refer to the Analyzing results - Screen Library Help topic fordetails about how to assess and extract good pharmacophore candidates from the results.To set up a Screen Library protocol1.Load the Pharmacophore | Screen Library protocol from the Protocols Explorer.The parameters display in the Parameters Explorer.2.On the Parameters Explorer, click in a cell for the Input Ligands parameterand click the button to specify the ligand source on the Specify Ligandsdialog. On the dialog, select all ligands from a Table Browser, a 3D Window, or a file.3.Specify the input source for the Input Pharmacophore parameter by openingthe Specify Query dialog. On the dialog, select the pharmacophore from a 3D Window or a file.4.Set the Minimum Features parameter. This is the minimum number of featuresthat each enumerated pharmacophore will have.5.Set the Maximum Features parameter. This is the maximum number of featuresthat each enumerated pharmacophore will have.6.Set the Maximum Subset of Pharmacophores parameter. This is the maximumnumber of pharmacophores that will be enumerated.7.The Total Number of Features and Number of Possible Pharmacophores parametersunder Advanced are provided to help with this. These are automaticallyupdated based on the pharmacophore model in the 3D Window, Minimum and Maximum Features parameters. If the Number of Possible Pharmacophores is greater than the Maximum Subset of Pharmacophores, the latter will be used. In thissituation, the pharmacophores are selected at random using selection without replacement so that the selection is sampled uniformly. To get more hits, increase the Maximum Subset of Pharmacophores parameter to a higher value.8.Set the remaining parameters as desired. Parameters presented in red arerequired.How to set up a Steric Refinement with Excluded Volumes runThe Steric Refinement with Excluded Volumes protocol adds excluded volumes to an input pharmacophore. The excluded volumes are placed on regions of space that are occupied by the inactive molecules, but not the active molecules.To set up a Steric Refinement with Excluded Volumes protocol:1.Load Pharmacophore | Steric Refinement with Excluded Volumes from theProtocols Explorer. The parameters display in the Parameters Explorer.2.Specify the input source for the Input Pharmacophore parameter by openingthe Specify Query dialog. On the dialog, select the pharmacophore from a 3D Window or a file.3.On the Parameters Explorer, click in a cell for the Input Active Ligandsparameter and click the button to specify the ligand source on theSpecify Ligands dialog. On the dialog, select all ligands from a Table Browser,a Graphics View, or a file. This parameter is required. The Input ActiveLigands parameter can contain the molecular property Principal to indicate active (2) and inactive molecules (0). If no value is set for these molecular properties, Principal is automatically set to 2.4.Optionally, on the Parameters Explorer, click in a cell for the Input InactiveLigands parameter and click the button to specify the ligand source onthe Specify Ligands dialog. On the dialog, select all ligands from a Table Browser, a 3D Window, or a file. The Input Inactive Ligands parameter isoptional. It is included so that it is possible to include a large set of molecules as inactive without having to set the Principal value. If the input ligands do not contain the molecular property Principal, the Principal value is automatically set to 0 (Inactive).5.Set the desired values for the remaining parameters. Parameters in red arerequired.Note.During the placement of excluded volumes, the MaxOmitFeat molecular property determines which mappings will be considered. A value of 1 for MaxOmitFeat means that all mappings where either all n or a subset of n-1features map will be considered. For more complicated data sets, it may be better to set MaxOmitFeat to 0 for the inactive molecules to avoid placing too many excluded volumes.。