De novo Molecular Design

Systematically examining current methods and strategies, De novo Molecular Design covers a wide range of molecular structures, from organic-chemical drugs to peptides, proteins and nucleic acids, in line with emerging new drug classes derived from biomacromolecules.

Systematically examining current methods and strategies, this ready reference covers a wide range of molecular structures, from organic-chemical drugs to peptides, Proteins and nucleic acids, in line with emerging new drug classes derived from biomacromolecules. A leader in the field and one of the pioneers of this young discipline has assembled here the most prominent experts from across the world to provide first-hand knowledge. While most of their methods and examples come from the area of pharmaceutical discovery and development, the approaches are equally applicable for chemical probes and diagnostics, pesticides, and any other molecule designed to interact with a biological system. Numerous images and screenshots illustrate the many examples and method descriptions. With its broad and balanced coverage, this will be the firststop resource not only for medicinal chemists, biochemists and biotechnologists, but equally for bioinformaticians and molecular designers for many years to come. From the content: Reaction-driven de novo design Adaptive methods in molecular design Design of ligands against multitarget profiles Free energy methods in ligand design Fragment-based de novo design Automated design of focused and target family-oriented compound libraries Molecular de novo design by nature-inspired computing 3D QSAR approaches to de novo drug design Bioisosteres in de novo design De novo design of peptides, proteins and nucleic acid structures, including RNA aptamers and many more.

Auteur
Gisbert Schneider is full professor of computer-assisted drug design at ETH Zürich, Switzerland. He studied biochemistry and computer science at the Free University of Berlin, Germany. After several international postdoctoral research activities he joined F. Hoffmann-La Roche Pharmaceuticals in Basel, Switzerland, where he headed the cheminformatics group. From 2002-2009 he was full professor of cheminformatics and bioinformatics (Beilstein Endowed Chair) at Goethe-University Frankfurt, Germany. Professor Schneider coined the terms "scaffold-hopping" and "frequent hitter" in drug design. His research activities concentrate on method development for adaptive molecular design and their tight integration with innovative chemical and biophysical techniques in drug discovery.

Contenu
Foreword Preface DE NOVO DESIGN: FROM MODELS TO MOLECULES Molecular Representation The Molecular Design Cycle Receptor-Ligand Interaction Modeling Fitness Landscapes Strategies for Compound Construction Strategies for Compound Scoring Flashback Forward: A Brief History of De Novo Drug Design Conclusions COPING WITH COMPLEXITY IN MOLECULAR DESIGN Introduction A Simple Model of Molecular Interactions Enhancements to the Simple Complexity Model Enumerating and Sampling the Complexity of Chemical Space Validation of the Complexity Model Reductionism and Drug Design Complexity and Information Content as a Factor in De Novo Design Complexity of Thermodynamic Entropy and Drug Design Complex Systems, Emergent Behavior, and Molecular Design THE HUMAN POCKETOME Predicted Pockets Compilation of the Validated Human Pocketome Diversity and Redundancy of the Human Pocketome Compound Activity Prediction by Ligand-Pocket Docking and Scoring Pocketome-Derived 3D Chemical Fields as Activity Prediction Models Clustering the Ligands by Function and Subpockets Conclusions STRUCTURE-BASED DE NOVO DRUG DESIGN Introduction Current Progress in SBDND Methodologies Recent Applications of Structure-Based De Novo Design Perspectives and Conclusion DE NOVO DESIGN BY FRAGMENT GROWING AND DOCKING Introduction Case Study I: High-Throughput Screening with Dr Feils Case Study II: Fragment-Based Drug Design with Dr Goode Conclusion HIT AND LEAD IDENTIFICATION FROM FRAGMENTS Introduction to FBDD Fragment Library Design Incorporating Computational Methods Fragment Screening Fragment Prioritization for Optimization Fragment Hit Expansion and Fragment Evolution Fragment Merging Principles Fragment Linking Principles Fragment-Assisted Drug Discovery (FADD) Conclusion PHARMACOPHORE-BASED DE NOVO DESIGN Introduction A Summary of the Algorithms of PhDD v1.0 An Introduction to the Modifications in the Updated Version of PhDD (v2.0) Validation of PhDD Concluding Remarks 3D-QSAR APPROACHES TO DE NOVO DRUG DESIGN Introduction Current Methods Leapfrog Recent Advances Conclusions LIGAND-BASED MOLECULAR DESIGN USING PSEUDORECEPTORS Introduction Pseudoreceptor Algorithms Successful Applications Overview Conclusions REACTION-DRIVEN DE NOVO DESIGN: A KEYSTONE FOR AUTOMATED DESIGN OF TARGET FAMILY-ORIENTED LIBRARIES Introduction Reaction-Driven Design: Tackling the Problem of Synthetic Feasibility Successful Applications of Reaction-Driven De Novo Design Reaction-Driven Design of Chemical Libraries Addressing Target Families Conclusions MULTIOBJECTIVE DE NOVO DESIGN OF SYNTHETICALLY ACCESSIBLE COUMPOUNDS Introduction Design of Synthetically Accessible Compounds Synthetic Accessibility Using Reaction Vectors De Novo Design Using Evolutionary Algorithms Conclusions DE NOVO DESIGN OF LIGANDS AGAINST MULTITARGET PROFILES Introduction Automating the Creativity of Ligand Design Evolutionary Algorithm Experimental Validation Reducing Antitarget Activity Optimizing D4 Receptor Potency Designing Novel Ligands to a Defined Profile Conclusion CONSTRUCTION OF DRUG-LIKE COMPOUNDS BY MARKOV CHAINS Introduction FOG Algorithm and Library Generation Applications Conclusion COPING WITH COMBINATORIAL SPACE IN MOLECULAR DESIGN Introduction Chemical Space Combinatorial Space Visualization Conclusion FRAGMENT-BASED DESIGN OF FOCUSED COMPOUND LIBRARIES Introduction General Workflow Fragment Space Query FTrees Fragment Space Search Scaffold Selection Design of Focused Libraries Application Example Summary and Conclusions FREE ENERGY METHODS IN LIGAND DESIGN Free Energy (FE) Methods in Lead Optimization (LO) The Variety of In Silico Binding Affinity Methods The Choice of a Method for Calculating Binding FE Experimental Data Current Issues Practical Examples Miscellaneous Issues Best Practices Conclusions and Outlook BIOISOSTERES IN DE NOVO DESIGN Introduction History of Isosterism and Bioisosterism Methods for Bioisosteric Replacement Exemplar Applications Conclusions PEPTIDE DESIGN BY NATURE-INSPIRED ALGORITHMS Template-Based Design Nature-Inspired Optimization Worked Example: De Novo Design of MHC-I Binding Peptides by Ant Colony Optimization Chemical Modification Conclusions and Outlook DE NOVO COMPUTATIONAL PROTEIN DESIGN Introduction Elements of Computational Protein Design Efforts in Theoretically Guided Protein Design Conclusion DE NOVO DESIGN OF NUCLEIC ACID STRUCTURES Introduction DNA-Branched Structures Scaffolded DNA Origami Design Alternative DNA Designs: Between Junctions and Origami Conclusions RNA APTAMER DESIGN Aptamers and Design Riboswitches and Aptamers SELEX Speeding Up SELEX by Computational Methods Structures and Probing Methods Functional Analyses (In Vitro and In Vivo) Problems Future Perspectives Index