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« LigandScout 3.1 Overview 1. Help Overview 2. Introduction to LigandScout 2.1 What's New in LigandScout 3? 2.2 Installing and Starting LigandScout 2.3 Visual Semantics 2.4 LigandScout Graphical User Interface 3. File Handling, Data Management and Networking 3.1 Importing and Exporting Files 3.2 Retrieving PDB Complexes Online 3.3 Local and Shared Repository 3.4 Sessions 3.5 Networking 4. LigandScout Perspectives 4.1 Basic User Interface Modules 4.2 Structure-Based Modeling Perspective 4.3 Ligand-Based Modeling Perspective 4.4 Alignment Perspective 4.5 Screening Perspective 5. Introduction to Pharmacophore Modeling 5.1 Pharmacophore Modeling 5.2 Pharmacophore Feature Definitions 5.3 Editing a Pharmacophore Model 6. Structure-Based Pharmacophore Design 6.1 Structure-Based Pharmacophores 6.2 Creating Structure-Based Pharmacophores 7. Pharmacophore Alignment 7.1 Aligning Pharmacophores and Molecules 7.2 Shared Feature Pharmacophore 7.3 Merged Feature Pharmacophore 8. Ligand-Based Pharmacophore Design 8.1 Ligand-Based Pharmacophores 8.2 Creating Ligand-Based Pharmacophores 9. Virtual Screening 9.1 Virtual Screening in LigandScout 9.2 Preparing a Pharmacophore for Virtual Screening with External Applications 10. LigandScout Settings: Preferences 10.1 Structure-Based Modeling Settings 10.2 Ligand-Based Modeling Settings 10.3 Chemistry Settings 10.4 Library Screening Settings 10.5 Alignment Settings 10.6 Rendering Settings 10.7 Program and Network Settings A. Appendix A.1 LigandScout Menu Reference A.2 LigandScout Icons Reference A.3 LigandScout Keyboard Shortcuts A.4 LigandScout Mouse Bindings A.5 Network Administrator Guide A.6 Command Line Usage A.7 Scoring Function A.8 Calculation of MMFF94 Binding Enthalpies A.9 Primary Literature Index	Table of Contents 1. Help Overview 2. Introduction to LigandScout What's New in LigandScout 3? Installing and Starting LigandScout Visual Semantics LigandScout Graphical User Interface 3. File Handling, Data Management and Networking Importing and Exporting Files Retrieving PDB Complexes Online Local and Shared Repository Sessions Networking 4. LigandScout Perspectives Basic User Interface Modules Structure-Based Modeling Perspective Ligand-Based Modeling Perspective Alignment Perspective Screening Perspective 5. Introduction to Pharmacophore Modeling Pharmacophore Modeling Pharmacophore Feature Definitions Editing a Pharmacophore Model 6. Structure-Based Pharmacophore Design Structure-Based Pharmacophores Creating Structure-Based Pharmacophores 7. Pharmacophore Alignment Aligning Pharmacophores and Molecules Shared Feature Pharmacophore Merged Feature Pharmacophore 8. Ligand-Based Pharmacophore Design Ligand-Based Pharmacophores Creating Ligand-Based Pharmacophores 9. Virtual Screening Virtual Screening in LigandScout Preparing a Pharmacophore for Virtual Screening with External Applications 10. LigandScout Settings: Preferences Structure-Based Modeling Settings Ligand-Based Modeling Settings Chemistry Settings Library Screening Settings Alignment Settings Rendering Settings Program and Network Settings A. Appendix LigandScout Menu Reference LigandScout Icons Reference LigandScout Keyboard Shortcuts LigandScout Mouse Bindings Network Administrator Guide Command Line Usage Scoring Function Calculation of MMFF94 Binding Enthalpies Primary Literature Index
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Page designed & authored by G. Wolber

Inte:Ligand: Your partner for in-silico drug discovery

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« LigandScout 3.1 Overview

1. Help Overview

2. Introduction to LigandScout

2.1 What's New in LigandScout 3?
2.2 Installing and Starting LigandScout
2.3 Visual Semantics
2.4 LigandScout Graphical User Interface

3. File Handling, Data Management and Networking

3.1 Importing and Exporting Files
3.2 Retrieving PDB Complexes Online
3.3 Local and Shared Repository
3.4 Sessions
3.5 Networking

4. LigandScout Perspectives

4.1 Basic User Interface Modules
4.2 Structure-Based Modeling Perspective
4.3 Ligand-Based Modeling Perspective
4.4 Alignment Perspective
4.5 Screening Perspective

5. Introduction to Pharmacophore Modeling

5.1 Pharmacophore Modeling
5.2 Pharmacophore Feature Definitions
5.3 Editing a Pharmacophore Model

6. Structure-Based Pharmacophore Design

6.1 Structure-Based Pharmacophores
6.2 Creating Structure-Based Pharmacophores

7. Pharmacophore Alignment

7.1 Aligning Pharmacophores and Molecules
7.2 Shared Feature Pharmacophore
7.3 Merged Feature Pharmacophore

8. Ligand-Based Pharmacophore Design

8.1 Ligand-Based Pharmacophores
8.2 Creating Ligand-Based Pharmacophores

9. Virtual Screening

9.1 Virtual Screening in LigandScout
9.2 Preparing a Pharmacophore for Virtual Screening with External Applications

10. LigandScout Settings: Preferences

10.1 Structure-Based Modeling Settings
10.2 Ligand-Based Modeling Settings
10.3 Chemistry Settings
10.4 Library Screening Settings
10.5 Alignment Settings
10.6 Rendering Settings
10.7 Program and Network Settings

A. Appendix

A.1 LigandScout Menu Reference
A.2 LigandScout Icons Reference
A.3 LigandScout Keyboard Shortcuts
A.4 LigandScout Mouse Bindings
A.5 Network Administrator Guide
A.6 Command Line Usage
A.7 Scoring Function
A.8 Calculation of MMFF94 Binding Enthalpies
A.9 Primary Literature

Index

Aligning Pharmacophores and Molecules

Aligning Pharmacophores and Molecules by Features

General

LigandScout supports feature-based alignments of pharmacophores and molecules in arbitrary combinations. Alignments are always performed pairwise no matter how many elements are to be aligned. Therefore, it is necessary to mark one structure as a reference element. In case the user did not specify a reference element explicitly, LigandScout will automatically choose one element from the set of selected elements. All other selected elements will be aligned to this reference element .

A single alignment is based on matched chemical features (feature pairs) where one feature must be the reference element's feature set and the other must be from the feature set of the element to be aligned to the reference element. For pharmacophores these chemical features are given explicitly. However, for molecules these features have to be derived during the alignment algorithm and for the sake of clarity these are not visible to the user.

There are various ways to adjust the alignment algorithm. Please have a look at the section called “Alignment Settings” for details. We refer to the Copyboard Widget for more information on how to add pharmacophores and molecules to the Alignment List. Possible interactions in the Alignment Perspective are discussed in the the section called “Alignment Panel” .

Performing Alignments

Setting the Reference Element (Optional)

You can set a reference element prior to perform the alignment by selecting one element in the Alignment List and clicking the Set Reference icon. Please note that setting a reference element is to be seen as a hint to the alignment algorithm. If the reference element was set and the reference element is also part of the selected elements to be aligned, this reference element will be used during alignment. In all other cases (no reference element set, reference element set but not contained in the selected elements) an arbitrary reference element will be chosen automatically.

Aligning Selected Elements

All elements which will be selected in the Alignment List will be aligned to a reference element. This reference element can be set by the user or will be chosen automatically as described above. To perform an alignment, select two or more elements in the Alignment List. This should look like the following image where pharmacophores of ligands of complexes 1ke5 and 1ke6 were selected and 1ke6 was set to be the reference element.

Figure 7.1. Before Alignment

After clicking the icon Align Selected Elements LigandScout will calculate one or several alignments and present them to the user as illustrated in the image below. The activated slider indicates that there are several alignments available. Information about each alignment are found in the Alignment Details View , e.g., the associated RMS (root mean squared) value of the valid matched feature deviances is shown as well as the number of valid matched features.

Figure 7.2. After Alignment

There are cases where LigandScout will provide just a single alignment:

Three or more elements will be aligned to each other
A perfect alignment was found (usually a molecule to its own pharmacophore, or aligning two instances of the same structure)

Aligning Pharmacophores and Molecules by Reference Points

General

LigandScout supports alignments of pharmacophores and molecules with respect to the protein environment. This is a useful feature to investigate protein-ligand complexes of structurally related targets but also to generate shared feature pharmacophores. In this way the user is able to directly compare the absolute position of one or several ligands within the aligned binding site. For this approach, the investigated proteins structures have to show a certain degree of similarity, in order to achieve a meaningful structural alignment.

Performing Alignments

First, check the Show Advanced Options Box in the Alignment Perspective . LigandScout now offers both alignment modes: The Feature-Based Alignment mode and the Reference Points-Based Alignment mode. Activate the latter one and select the pharmacophore and/or molecules you want to align. Clicking onto the icon Align Selected Elements calculates the aligment of these elements with respect to their protein environment. In other words, LigandScout aligns the protein residues (which is by default not visible in the Alignment Perspective) of all selected elements in order to overlay the pharmacophores and molecules according to their position in the binding sites.

You can visualize the protein alignment by toggling on the reference points in the Hierarchy View or select in the menu Render Control > Show Reference Points in the Alignment Perspective. The protein residues will thereby be illustrated as small circles. In the same menu, Render Control > Show Reference Point Names allows you to place the residue identifiers on these reference points. Show Reference Point Tethers visualizes the affiliation of corresponding protein reference points with tethers.

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Chapter 7. Pharmacophore Alignment	Home	Shared Feature Pharmacophore

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Page designed & authored by G. Wolber

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