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Virtual Screening: Principles, Challenges, and Practical Guidelines, Volume 48

Christoph Sotriffer (Editor), Raimund Mannhold (Series Editor), Hugo Kubinyi (Series Editor), Gerd Folkers (Series Editor)
ISBN: 978-3-527-32636-5
550 pages
February 2011
Virtual Screening: Principles, Challenges, and Practical Guidelines, Volume 48 (3527326367) cover image
Drug discovery is all about finding small molecules that interact in a desired way with larger molecules, namely proteins and other macromolecules in the human body. If the three-dimensional structures of both the small and large molecule are known, their interaction can be tested by computer simulation with a reasonable degree of accuracy. Alternatively, if active ligands are already available, molecular similarity searches can be used to find new molecules. This virtual screening can even be applied to compounds that have yet to be synthesized, as opposed to "real" screening that requires cost- and labor-intensive laboratory testing with previously synthesized drug compounds.
Unique in its focus on the end user, this is a real "how to" book that does not presuppose prior experience in virtual screening or a background
in computational chemistry. It is both a desktop reference and practical guide to virtual screening applications in drug discovery, offering a comprehensive and up-to-date overview. Clearly divided into four major sections, the first provides a detailed description of the methods required for and applied in virtual screening, while the second discusses the most important challenges in order to improve the impact and success of this technique. The third and fourth, practical parts contain practical guidelines and several case studies covering the most
important scenarios for new drug discovery, accompanied by general guidelines for the entire workflow of virtual screening studies.
Throughout the text, medicinal chemists from academia, as well as from large and small pharmaceutical companies report on their experience and pass on priceless practical advice on how to make best use of these powerful methods.
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List of Contributors.


A Personal Foreword.

Part One Principles.

1 Virtual Screening of Chemical Space: From Generic Compound Collections to Tailored Screening Libraries (Markus Boehm).

1.1 Introduction.

1.2 Concepts of Chemical Space.

1.3 Concepts of Druglikeness and Leadlikeness.

1.4 Diversity-Based Libraries.

1.5 Focused Libraries.

1.6 Virtual Combinatorial Libraries and Fragment Spaces.

1.7 Databases of Chemical and Biological Information.

1.8 Conclusions and Outlook.

1.9 Glossary.


2 Preparing and Filtering Compound Databases for Virtual and Experimental Screening (Maxwell D. Cummings, Éric Arnoult, Christophe Buyck, Gary Tresadern, Ann M. Vos, and Jörg K. Wegner).

2.1 Introduction.

2.2 Ligand Databases.

2.3 Considering Physicochemical Properties.

2.4 Undesirables.

2.5 Property-Based Filtering for Selected Targets.

2.6 Summary.


3 Ligand-Based Virtual Screening (Herbert Koeppen, Jan Kriegl, Uta Lessel, Christofer S. Tautermann, and Bernd Wellenzohn).

3.1 Introduction.

3.2 Descriptors.

3.3 Search Databases and Queries.

3.4 Virtual Screening Techniques.

3.5 Conclusions.


4 The Basis for Target-Based Virtual Screening: Protein Structures (Jason C. Cole, Oliver Korb, Tjelvar S.G. Olsson, and John Liebeschuetz).

4.1 Introduction.

4.2 Selecting a Protein Structure for Virtual Screening.

4.3 Setting Up a Protein Model for vHTS.

4.4 Summary.

4.5 Glossary of Crystallographic Terms.


5 Pharmacophore Models for Virtual Screening (Patrick Markt, Daniela Schuster, and Thierry Langer).

5.1 Introduction.

5.2 Compilation of Compounds.

5.3 Pharmacophore Model Generation.

5.4 Validation of Pharmacophore Models.

5.5 Pharmacophore-Based Screening.

5.6 Postprocessing of Pharmacophore-Based Screening Hits.

5.7 Pharmacophore-Based Parallel Screening.

5.8 Application Examples for Synthetic Compound Screening.

5.9 Application Examples for Natural Product Screening.

5.9.10 Pharmacophore-Based Parallel Screening of Natural Products.

5.10 Conclusions.


6 Docking Methods for Virtual Screening: Principles and Recent Advances (Didier Rognan).

6.1 Principles of Molecular Docking.

6.2 Docking-Based Virtual Screening Flowchart.

6.3 Recent Advances in Docking-Based VS Methods.

6.4 Future Trends in Docking.


Part Two Challenges.

7 The Challenge of Affinity Prediction: Scoring Functions for Structure-Based Virtual Screening (Christoph Sotriffer and Hans Matter).

7.1 Introduction.

7.2 Physicochemical Basis of Protein–Ligand Recognition.

7.3 Classes of Scoring Functions.

7.4 Interesting New Approaches to Scoring Functions.

7.5 Comparative Assessment of Scoring Functions.

7.6 Tailoring Scoring Strategies in Virtual Screening.

7.7 Caveats for Development of Scoring Functions.

7.8 Conclusions.


8 Protein Flexibility in Structure-Based Virtual Screening: From Models to Algorithms (Angela M. Henzler and Matthias Rarey).

8.1 How Flexible Are Proteins? – A Historical Perspective.

8.2 Flexible Protein Handling in Protein–Ligand Docking.

8.3 Flexible Protein Handling in Docking-Based Virtual Screening.

8.4 Summary.


9 Handling Protein Flexibility in Docking and High-Throughput Docking: From Algorithms to Applications (Claudio N. Cavasotto).

9.1 Introduction: Docking and High-Throughput Docking in Drug Discovery.

9.2 The Challenge of Accounting for Protein Flexibility in Docking.

9.3 Accounting for Protein Flexibility in Docking-Based Drug Discovery and Design.

9.4 Conclusions.


10 Consideration of Water and Solvation Effects in Virtual Screening (Johannes Kirchmair, Gudrun M. Spitzer, and Klaus R. Liedl).

10.1 Introduction.

10.2 Experimental Approaches for Analyzing Water Molecules.

10.3 Computational Approaches for Analyzing Water Molecules.

10.4 Water-Sensitive Virtual Screening: Approaches and Applications.

10.5 Conclusions and Recommendations.


Part Three Applications and Practical Guidelines.

11 Applied Virtual Screening: Strategies, Recommendations, and Caveats (Dagmar Stumpfe and Jürgen Bajorath).

11.1 Introduction.

11.2 What Is Virtual Screening?

11.3 Spectrum of Virtual Screening Approaches.

11.4 Molecular Similarity as a Foundation and Caveat of Virtual Screening.

11.5 Goals of Virtual Screening.

11.6 Applicability Domain.

11.7 Reference and Database Compounds.

11.8 Biological Activity versus Compound Potency.

11.9 Methodological Complexity and Compound Class Dependence.

11.10 Search Strategies and Compound Selection.

11.11 Virtual and High-Throughput Screening.

11.12 Practical Applications: An Overview.

11.13 LFA-1 Antagonist.

11.14 Selectivity Searching.

11.15 Concluding Remarks.


12 Applications and Success Stories in Virtual Screening (Hans Matter and Christoph Sotriffer).

12.1 Introduction.

12.2 Practical Considerations.

12.3 Successful Applications of Virtual Screening.

12.4 Conclusion.


Part Four Scenarios and Case Studies: Routes to Success.

13 Scenarios and Case Studies: Examples for Ligand-Based Virtual Screening (Trevor Howe, Daniele Bemporad, and Gary Tresadern).

13.1 Introduction.

13.2 1D Ligand-Based Virtual Screening.

13.3 2D Ligand-Based Virtual Screening.

13.4 3D Ligand-Based Virtual Screening.

13.5 Summary.


14 Virtual Screening on Homology Models (Róbert Kiss and György M. Keseru).

14.1 Introduction.

14.2 Homology Models versus Crystal Structures: Comparative Evaluation of Screening Performance.

14.3 Challenges of Homology Model-Based Virtual Screening.

14.4 Case Studies.

15 Target-Based Virtual Screening on Small-Molecule Protein Binding Sites (Ralf Heinke, Urszula Uciechowska, Manfred Jung, and Wolfgang Sippl).

15.1 Introduction.

15.2 Structure-Based VS for Histone Arginine Methyltransferase PRMT1 Inhibitors.

15.3 Identification of Nanomolar Histamine H3 Receptor Antagonists by Structure- and Pharmacophore-Based VS.

15.4 Summary.


16 Target-Based Virtual Screening to Address Protein–Protein Interfaces (Olivier Sperandio, Maria A. Miteva, and Bruno O. Villoutreix).

16.1 Introduction.

16.2 Some Recent PPIM Success Stories.

16.3 Protein–Protein Interfaces.

16.4 PPIMs. Chemical Space and ADME/Tox Properties.

16.5 Drug Discovery, Chemical Biology, and In Silico Screening Methods: Overview and Suggestions for PPIM Search.

16.6 Case Studies.

16.7 Conclusions and Future Directions.


17 Fragment-Based Approaches in Virtual Screening (Danzhi Huang and Amedeo Caflisch).

17.1 Introduction.

17.2 In Silico Fragment-Based Approaches.

17.3 Our Approach to High-Throughput Fragment-Based Docking.

17.4 Lessons Learned from Our Fragment-Based Docking.

17.5 Challenges of Fragment-Based Approaches.


Appendix A: Software Overview.

Appendix B: Virtual Screening Application Studies.


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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.
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"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)

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