InhaltsangabePreface PART I: Principles VIRTUAL SCREENING OF CHEMICAL SPACE: FROM GENERIC COMPOUND COLLECTIONS TO TAILORED SCREENING LIBRARIES Introduction Concepts of Chemical Space Concepts of Druglikeness and Leadlikeness DiversityBased Libraries Focused Libraries Virtual Combinatorial Libraries and Fragment Spaces Databases of Chemical and Biological Information Conclusions and Outlook Glossary PREPARING AND FILTERING COMPOUND DATABASES FOR VIRTUAL AND EXPERIMENTAL SCREENING Introduction Ligand Databases Considering Physicochemical Properties Undesirables PropertyBased Filtering for Selected Targets Summary LIGANDBASED VIRTUAL SCREENING Introduction Descriptors Search Databases and Queries Virtual Screening Techniques Conclusions THE BASIS FOR TARGET-BASED VIRTUAL SCREENING: PROTEIN STRUCTURES Introduction Selecting a Protein Structure for Virtual Screening Setting Up a Protein Model for vHTS Summary Glossary of Crystallographic Terms PHARMACOPHORE MODELS FOR VIRTUAL SCREENING Introduction Compilation of Compounds Pharmacophore Model Generation Validation of Pharmacophore Models Pharmacophore-Based Screening Postprocessing of Pharmacophore-Based Screening Hits Pharmacophore-Based Parallel Screening Application Examples for Synthetic Compound Screening Application Examples for Natural Product Screening Conclusions DOCKING METHODS FOR VIRTUAL SCREENING: PRINCIPLES AND RECENT ADVANCES Principles of Molecular Docking DockingBased Virtual Screening Flowchart Recent Advances in Docking-Based VS Methods Future Trends in Docking PART II: Challenges THE CHALLENGE OF AFFINITY PREDICTION: SCORING FUNCTIONS FOR STRUCTURE-BASED VIRTUAL SCREENING Introduction Physicochemical Basis of Protein-Ligand Recognition Classes of Scoring Functions Interesting New Approaches to Scoring Functions Comparative Assessment of Scoring Functions Tailoring Scoring Strategies in Virtual Screening Caveats for Development of Scoring Functions Conclusion PROTEIN FLEXIBILITY IN STRUCTURE-BASED VIRTUAL SCREENING: FROM MODELS TO ALGORITHMS How Flexible Are Proteins? - A Historical Perspective Flexible Protein Handling in Protein-Ligand Docking Flexible Protein Handling in Docking-Based Virtual Screening Summary HANDLING PROTEIN FLEXIBILITY IN DOCKING AND HIGH-THROUGHPUT DOCKING: FROM ALGORITHMS TO APPLICATIONS Introduction: Docking and High-Throughput Docking in Drug Discovery The Challenge of Accounting for Protein Flexibility in Docking Accounting for Protein Flexibility in Docking-Based Drug Discovery and Design Conclusions CONSIDERATION OF WATER AND SOLVATION EFFECTS IN VIRTUAL SCREENING Introduction Experimental Approaches for Analyzing Water Molecules Computational Approaches for Analyzing Water Molecules WaterSensitive Virtual Screening: Approaches and Applications Conclusions and Recommendations PART III: Applications and Pracitcal Guidelines APPLIED VIRTUAL SCREENING: STRATEGIES, RECOMMENDATIONS, AND CAVEATS Introduction What Is Virtual Screening? Spectrum of Virtual Screening Approaches Molecular Similarity as a Foundation and Caveat of Virtual Screening Goals of Virtual Screening Applicability Domain Reference and Database Compounds Biological Activity versus Compound Potency Methodological Complexity and Compound Class Dependence Search Strategies and Compound Selection Virtual and High-Throughput Screening Practical Applications: An Overview LFA1 Antagonist Selectivity Searching Concluding Remarks APPLICATIONS AND SUCCESS STORIES IN VIRTUAL SCREENING Introduction Practical Considerations Successful Applications of Virtual Screening Conclusions PART IV: Scenarios and Case Studies: Routes to Success SCENARIOS AND CASE STUDIES: EXAMPLES FOR LIGAND-BASED VIRTUAL SCREENING Introduction 1D LigandBased Virtual Screening 2D LigandBased Virtual Screening 3D LigandBased Virtual Screening Summary VIRTUAL SCREENING ON HOMOLOGY M

Christoph Sotriffer is Professor for Pharmaceutical Chemistry at the University ofWürzburg, Germany. He graduated as a chemist from the University of Innsbruck, Austria, where he obtained his PhD in 1999. After conducting postdoctoral research at the University of California, San Diego, USA, and the University of Marburg, Germany, he moved to the University ofWürzburg in 2006, where he has built a research group for computational medicinal chemistry. Besides structure-based drug design and virtual screening, his prime scientific interest is the computational analysis and prediction of protein-ligand interactions. His work was awarded by the Austrian Chemical Society GÖCH in 2005 and the German Chemical and Pharmaceutical Societies GDCh and DPhG in 2007.

I PRINCIPLES Virtual screening of chemical space: From generic compound databases to focused screening libraries Preparing and Filtering Compound Databases for Virtual and Experimental Screening Ligand-based virtual screening The basis for target-based virtual screening: Protein structures Pharmacophore models for virtual screening Docking methods for virtual screening II CHALLENGES The challenge of affinity prediction: Scoring functions for virtual screening Protein flexibility in structure-based virtual screening: From models to algorithms Handling protein flexibility in docking and high-throughput docking: From algorithms to applications Consideration of water and solvation effects in virtual screening III APPLICATIONS AND PRACTICAL GUIDELINES Applied virtual screening: Strategies, recommendations, and caveats Applications and Success stories in virtual screening IV SCENARIOS AND CASE STUDIES:ROUTES TO SUCCESS Examples for ligand-based virtual screening Examples for screening based on homology models Target-based virtual screening on small molecule protein binding sites Target-based virtual screening to address protein-protein interfaces Fragment-based approaches in virtual screening