LigandScout User Manual

1 LigandScout User ManualLigandScout User ManualiiiTable of Contents1. Introduction to LigandScout .. What's New in LigandScout .. Installing and Starting LigandScout .. Visual Semantics .. LigandScout Graphical User Interface .. 92. File Handling, Data Management and Networking .. Importing and Exporting Files .. Retrieving PDB Complexes Online .. Local and Shared Repository .. Handling the Repository .. Sessions .. Handling Sessions .. Networking .. iworker .. Network Monitor .. 213. LigandScout Perspectives .. Basic User Interface Modules .. 3D View .. 2D View .. 3D Widgets .. Hierarchy View .. Library View .. Structure-Based Modeling Perspective.

2 PDB View .. Bookmark View .. Ligand-Based Modeling Perspective .. Importing Ligands .. Navigation and Working with the Tool Bar .. Biasing Pharmacophore Generation .. Alignment Perspective .. Alignment Panel .. Screening Perspective .. Screening Panel .. Library View .. 504. Introduction to Pharmacophore Modeling .. Pharmacophore Modeling .. Pharmacophore Definition .. Pharmacophore Feature Definitions .. Pharmacophore Feature Constraint Types .. Pharmacophore Feature Definitions .. Editing a Pharmacophore Model .. 565. Structure-Based Pharmacophore Design .. Structure-Based Pharmacophores .. Why Use Structure-Based Pharmacophores?

3 Basic Workflow .. Creating Structure-Based Pharmacophores .. Data Import and Structure Preparation .. Automated Generation of Structure-Based Pharmacophores .. 606. Pharmacophore Alignment .. Aligning Pharmacophores and Molecules .. Aligning Pharmacophores and Molecules by Features .. Aligning Pharmacophores and Molecules by Reference Points .. Shared Feature Pharmacophore .. Creating a Shared Feature Pharmacophore .. Merged Feature Pharmacophore .. 66 LigandScout User Automatically Merge Pharmacophores .. Manually Merge Pharmacophores .. Combine Features in One Pharmacophore .. 687. Ligand-Based Pharmacophore Design .. Ligand-Based Pharmacophores .. Why Use Ligand-Based Pharmacophores?

4 Basic Workflow .. Creating Ligand-Based Pharmacophores .. Define and prepare Ligand-Set .. Performing Ligand-Based Pharmacophore Creation .. Resulting Ligand-based Pharmacophore Models .. 738. Virtual Screening .. Virtual Screening in LigandScout .. Pharmacophore and Molecule Library Preparation .. Run Virtual Screening .. Screening Results .. Preparing a Pharmacophore for Virtual Screening with External 769. LigandScout Settings: Preferences .. Structure-Based Modeling Settings .. PDB Interpretation .. Distance Ranges .. Hydrogen Bonding .. Metal Binding .. Hydrophobicity .. Aromatic Interactions .. Ligand-Based Modeling Settings.

5 Settings and Scoring .. Conformer Generation .. Clustering .. Chemistry Settings .. Tautomerization .. Tautomer Filters .. Force Field: MMFF94 .. Force Field: Minimization .. Library Screening Settings .. Alignment Settings .. Alignment .. Rendering Settings .. 3D General Settings .. 3D Renderer Style .. 2D Depiction .. Program and Network Settings .. Main Settings .. PDB and Proxy .. Distributed Calculation .. 103A. Appendix .. LigandScout Menu Reference .. LigandScout Icons Reference .. LigandScout Keyboard Shortcuts .. LigandScout Mouse Bindings .. Command Line Usage .. Scoring Function.

6 Primary Literature .. 139 Index .. 1425 Chapter 1. Introduction toLigandScoutTable of What's New in LigandScout .. Installing and Starting LigandScout .. Visual Semantics .. LigandScout Graphical User Interface .. 9 LigandScout is a powerful structure- and ligand-based pharmacophore model generator based onsophisticated algorithms for performing alignments and interpreting and customizing ligand-macro-molecule extracts and interprets ligands and their macromolecular environment from PDB files andautomatically creates and visualizes advanced 3D pharmacophore models supporting multiple featuresper heavy atom to broaden the scope of a single model. A wide range of powerful editing tools (2 DView and 3D View) lets you generate customized, highly specific pharmacophore models within a fewseconds.

7 Excluded volume recognition and the resulting excluded volume coats drastically increaseselectivity by considering sterical characteristics of the binding site. Moreover, LigandScout supportsthe generation of pharmacophore models based on molecules injected into the binding site and suppliesa Library View for the investigation of docking poses and viewing results of virtual screening in the of the conformational space of ligands, clustering and alignment methods help to search forcommon feature arrangements. This is especially useful when binding site interactions are not a consensus pattern from a set of ligands binding to one particular macromolecule is a furtherstep in drug development. Rapid and accurate in-silico screening of compound libraries is integratedinto LigandScout along with tools to analyze the performance of the Manual documents all LigandScout features and gives workflow guidelines for the generation ofstructure-based pharmacophores, ligand-based pharmacophores, virtual screening of molecule librariesand pharmacophore preparation for external virtual screening 's New in LigandScout and Starting LigandScout .

8 The 3D Graphical User InterfaceIntroduction to What's New in LigandScout features introduced to LigandScout Structure Optimization by MMF94 Force Calculation of Tasks through the Network to increase Execution Hot TopicsTautomersTautomeric rearrangements of a molecule lead to distinct equilibrated structural states of the samechemical compound and thus have an influence on nearly all aspects of computer-based chemical dataprocessing. Especially for structure-based pharmacophore modeling of ligand-protein complexes, tau-tomeric rearrangements are crucial for the presence or absence of possible H-bonding interactions dueto changing H-donor/H-acceptor properties. LigandScout provides a rule-based ligand-side tautomerenumeration and ranking procedure that considers both geometrical constraints imposed by the confor-mation of the bound ligand as well as intra- and inter-molecular energetic FieldsLigandScout provides a full fledged, test-suite conforming MMFF94 implementation for the energy cal-culation and geometry optimization of molecular structures.

9 You can calculate the strain energy of com-pounds in a database, energy-minimize the structure of free molecules or optimize ligands within abinding pocket. The parameters of the MMFF94 force field can be customized. For instance, you candefine which components of the force field have to be considered and specify parameters for severalinteractions ( distance cutoffs for Van der Waals and electrostatic interactions). During a structureoptimization process, SMARTS pattern defined parts of the ligand or molecular environment can bekept AnalysisThe right ligand conformation is a prerequisite for an energetically favorable interaction with the targetreceptor. Thus, consideration of multiple ligand conformations can increase significantly the quality andreliability of derived pharmacophore models.

10 LigandScout enables the creation of ligand-based phar-Introduction to LigandScout7macophores from single and multiple ligand conformations. Conformations are generated by OMEGA which can be customized freely to yield optimal of the crucial parts of ligand-based pharmacophore creation is the choice of ligands for the Train-ing-Set and Test-Set. LigandScout offers clustering methods to assist your decision. This functionalitygroups ligands according to their similarity to each other using distance calculation Installing and Starting LigandScoutThe current version of LigandScout is available via Internet download from Inte:Ligand [ ]. The LigandScout setup assistant will guide youthrough the installation process.