Virtual Screening

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.

Preface

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
Diversity-Based 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
Property-Based Filtering for Selected Targets
Summary

LIGAND-BASED 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
Docking-Based 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
Water-Sensitive 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
LFA-1 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 Ligand-Based Virtual Screening
2D Ligand-Based Virtual Screening
3D Ligand-Based Virtual Screening
Summary

VIRTUAL SCREENING ON HOMOLOGY MODELS
Introduction
Homology Models versus Crystal Structures: Comparative Evaluation of Screening Performance
Challenges of Homology Model-Based Virtual Screening
Case Studies

TARGET-BASED VIRTUAL SCREENING ON SMALL-MOLECULE PROTEIN BINDING SITES
Introduction
Structure-Based VS for Histone Arginine Methyltransferase PRMT1 Inhibitors
Identification of Nanomolar Histamine H3 Receptor Antagonists by Structure- and Pharmacophore-Based VS
Summary

TARGET-BASED VIRTUAL SCREENING TO ADDRESS PROTEIN-PROTEIN INTERFACES
Introduction
Some Recent PPIM Success Stories
Protein-Protein Interfaces
PPIM's Chemical Space and ADME/Tox Properties
Drug Discovery, Chemical Biology, and In Silico Screening Methods: Overview and Suggestions for PPIM Search
Case Studies
Conclusions and Future Directions

FRAGMENT-BASED APPROACHES IN VIRTUAL SCREENING
Introduction
In Silico Fragment-Based Approaches
Our Approach to High-Throughput Fragment-Based Docking
Lessons Learned from Our Fragment-Based Docking
Challenges of Fragment-Based Approaches

APPENDIX
Software Overview
Virtual Screening Application Studies

"Although mediocre quality and inconsistency of some of the figures and chemical structure drawings curbed my enthusiasm, I emphatically recommend this book to anyone who is avid of learning (more) about the current and future "state-of-the-science" in virtual screening." (Molecular Informatics, 2011)
"The book is well suited both for all practitioners in medicinal chemistry and for graduate students who want to learn how to apply virtual screening methodology." (International Journal Bioautomation, 2011)

"All scientists interested in the field will have an interest in reading it, whether for the bibliographic contents,
examples cited or principles broached. Students will find out "how to do it", whatever their intent is, which will
make this volume a useful handbook. No need to be an expert in the field or a computer specialist to give it a try." (ChemMedChem, 2011)

"This comprehensive and up-to-date review of the basic concepts and tools for virtual screening applications in drug discovery is part of the Methods and Principles in Medicinal Chemistry series, which has been a crucial source of information for medicinal chemists from both academia and pharmaceutical companies since 1993." (Doody s, 30 September 2011)

"Virtual Screening is a comprehensive and up-to-date overview, this is both a desktop reference and practical guide for virtual screening applications in drug discovery". (Laboratory Journal, 18 January 2011)