E-Book, Englisch, 356 Seiten, Web PDF
E-Book, Englisch, 356 Seiten, Web PDF
ISBN: 978-1-84755-887-9
Verlag: Royal Society of Chemistry
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)
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Weitere Infos & Material
Preface; 1 - Fragment Descriptors in SAR/QSAR/QSPR studies, molecular similarity analysis and in virtual screening; Introduction; Historical survey; Main characteristics of Fragment Descriptors; Types of Fragments; Simple Fixed Types; WLN and SMILES Fragments; Atom-Centered Fragments; Bond-Centered Fragments; Maximum Common Substructures; Atom Pairs and Topological Multiplets; Substituents and Molecular Frameworks; Basic Subgraphs; Mined Subgraphs; Random Subgraphs; Library Subgraphs; Fragments describing supramolecular systems and chemical reactions; Storage of fragments' information; Fragment's Connectivity; Generic Graphs; Labeling Atoms; Application in Virtual Screening and In Silico Design; Filtering; Similarity Search; SAR Classification (Probabilistic) Models; QSAR/QSPR Regression Models; In Silico Design; Limitations of Fragment Descriptors; Conclusion; 2 - Topological Pharmacophores; Introduction; 3D pharmacophore models and descriptors; Topological pharmacophores; Topological pharmacophores from 2D-aligments; Topological pharmacophores from 2D pharmacophore fingerprints; Topological index-based 'pharmacophores'?; Topological pharmacophores from 2D-aligments; Topological pharmacophores from pharmacophore fingerprints; Topological pharmacophore pair fingerprints; Topological pharmacophore triplets; Similarity searching with pharmacophore fingerprints - Technical Issues; Similarity searching with pharmacophore fingerprints - Some Examples; Machine-learning of Topological Pharmacophores from Fingerprints; Topological index-based 'pharmacophores'?; Conclusions; 3 - Pharmacophore-based Virtual Screening in Drug Discovery; Introduction; Virtual Screening Methods; Chemical Feature-based Pharmacophores; The Term "3D Pharmacophore"; Feature Definitions and Pharmacophore Representation; Hydrogen bonding interactions; Lipophilic areas; Aromatic interactions; Charge-transfer interactions; Customization and definition of new features; Current super-positioning techniques for aligning 3D pharmacophores and molecules; Generation and Use of Pharmacophore Models; Ligand-based Pharmacophore Modeling; Structure-based Pharmacophore Modeling; Inclusion of Shape Information; Qualitative vs. Quantitative Pharmacophore Models; Validation of Models for Virtual Screening; Application of Pharmacophore Models in Virtual Screening; Pharmacophore Models as Part of a Multi-Step Screening Approach; Antitarget and ADME(T) Screening Using Pharmacophores; Pharmacophore Models for Activity Profiling and Parallel Virtual Screening; Pharmacophore Method Extensions and Comparisons to Other Virtual Screening Methods; Topological Fingerprints; Shape-based Virtual Screening; Docking Methods; Pharmacophore Constraints Used in Docking; Further Reading; Summary and Conclusion; 4 - Molecular Similarity Analysis in Virtual Screening; Ligand-Based Virtual Screening; Foundations of Molecular Similarity Analysis; Molecular Similarity and Chemical Spaces; Similarity Measures; Activity Landscapes; Analyzing the Nature of Structure-Activity Relationships; Relationships between different SARs; SARs and target-ligand interactions; Qualitative SAR characterization; Quantitative SAR characterization; Implications for molecular similarity analysis and virtual screening; Strengths and Limitations of Similarity Methods; Conclusion and Future Perspectives; 5 - Molecular Field Topology Analysis in drug design and virtual screening; Introduction: local molecular parameters in QSAR, drug design and virtual screening; Supergraph-based QSAR models; Rationale and history; Molecular Field Topology Analysis (MFTA); General principles; Local molecular descriptors: facets of ligand-biotarget interaction; Construction of molecular supergraph; Formation of descriptor matrix; Statistical analysis; Applicability control; From MFTA model to drug design and virtual screening; MFTA models in biotarget and drug action analysis; MFTA models in virtual screening; MFTA-based virtual screening of compound databases; MFTA-based virtual screening of generated structure libraries; Conclusion; 6 - Probabilistic approaches in activity prediction; Introduction; Biological Activity; Dose-Effect Relationships; Experimental Data; Probabilistic Ligand-Based Virtual Screening Methods; Preparation of Training Sets; Creation of Evaluation Sets; Mathematical Approaches; Evaluation of Prediction Accuracy; Single-Targeted vs. Multi-Targeted Virtual Screening; PASS Approach; Biological Activities Predicted by PASS; Chemical Structure Description in PASS; SAR Base; Algorithm of Activity Spectrum Estimation; Interpretation of Prediction Results; Selection of the Most Prospective Compounds; Conclusions; 7 - Fragment-based de novo design of druglike molecules; Introduction;From Molecules to Fragments; From Fragments to Molecules; Scoring the Design; Conclusions and Outlook; 8 - Early ADME/T predictions: a toy or a tool?; Introduction; Which properties are important for early drug discovery?; Physico-chemical profiling; Lipophilicity; Solubility; Data availability and accuracy; Models; Why models don't work: the challenge of the Applicability Domain; AD based on similarity in the descriptor space; AD based on similarity in the property-based space; How reliable are predictions of physico-chemical properties?; Available Data for ADME/T biological properties; Absorption; Data; Models; Distribution; Data; Models; The usefulness of ADME/T models is limited by available data; Conclusions; 9 - Compound Library Design - Principles and Applications; Introduction to Compound Library Design; Methods for Compound Library Design; Design for Specific Biological Activities; Similarity Guided Design of Targeted Libraries; Diversity Based Design of General Screening Libraries; Pharmacophore Guided Design of Focused Compound Libraries; QSAR Based Targeted Library Design; Protein Structure Based Methods for Compound Library Design; Design for Developability or Drug-likeness; Rule & Alert Based Approaches; QSAR Based ADMET Models; Undesirable Functionality Filters; Design for Multiple Objectives and Targets Simultaneously; Concluding Remarks; 10 - Integrated Chemo- and Bioinformatics Approaches to Virtual Screening; Introduction; Availability of large compound collections for virtual screening; NIH Molecular Libraries Roadmap Initiative and the PubChem database; Other chemical databases in public domain; Structure based virtual screening; Major methodologies; Challenges and limitations of current approaches; The implementation of cheminformatics concepts in structure based virtual screening; Predictive QSAR models as virtual screening tools; Critical Importance of model validation; Applicability domains and QSAR model acceptability criteria; Predictive QSAR modeling workflow; Examples of application; Structure based chemical descriptors of protein ligand interface: the EnTESS method; Derivation of the EnTESS descriptors; Validation of the EnTESS descriptors for binding affinity prediction; Structure based cheminformatics approach to virtual screening: the CoLiBRI method; The representation of three-dimensional active sites in multidimensional chemistry space; The mapping between chemistry spaces of active sites and ligands; Summary and Conclusions