Chemogenomics: Methods and Applications (Methods in Molecular Biology, 575)

✍ Scribed by Edgar Jacoby (editor)

• Publisher: Humana
• Year: 2009
• Tongue: English
• Leaves: 324
• Category: Library

✦ Synopsis

Chemogenomics aims toward the systematic identification of small molecules that interact with the products of the genome and modulate their biological function. The establishment, analysis, prediction, and expansion of a comprehensive ligand–target SAR (structure–activity relationship) matrix has followed the elucidation of the human genome and presents a key scientific challenge for the twenty-first century. The anno- tion and knowledge-based exploration of the ligand–target SAR matrix is then expected to impact science greatly. Progress alongside this challenge without a doubt will c- tribute to further the fundamental understanding of the biological function of the individual proteins and ultimately provide a basis for the discovery of new and better therapies for diseases. While historically the chemogenomics approach is based on efforts that systematically explore target gene families, today broader in vitro and in silico approaches are available to encompass wider genomes. In this book, experts from academia and industry outline relevant aspects of ch- istry, biology, and molecular informatics which are the cornerstones of chemogenomics. General introductory chapters are combined with chapters describing methods and pro- cols, which are the gold standard of the Methods in Molecular Biology book series.

✦ Table of Contents

Jacoby_FM_O
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Chapter 1
Organizing Bioactive Compound Discovery in Target Families
3. Exploring Chemical Space
4.1. G-Protein-Coupled Receptors (GPCRs)
4.2. Kinases
4.3. Proteases
References
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Chapter 2
Compound Library Design for Target Families
2.1. Databases
2.2. Experimental Dataset
2.3. Software
3.1. Som
3.1.1. The Main Concept of SOM
3.1.2. Import From Database
3.1.3. Descriptor Calculation
3.1.4. Descriptor Selection
3.1.5. Database Preprocessing
3.1.6. Kohonen Map Generation
3.3. Similarity Across the Chemokine Receptor Superfamily
3.4. Internal Database Analysis
3.4.2. Descriptor Calculation and Mapping
3.5. Conclusion
References
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Chapter 3
Targeting the Purinome
6.1. Phosphodiesterases – an Accessible, Readily Druggable Active Site
6.2. Protein Kinases – Achieving Selectivity in a Family with High Homology
6.2.1. The Gatekeeper Residue
6.2.2. The XDFG Motif
6.2.3. The Selectivity Region on the aD Helix
6.2.4. The Span of Residues Between the Gatekeeper and the Ribose-Binding Site
6.2.5. Inhibitor-Specific Conformations
6.3. Eg5 (Motor Protein and Mitotic Kinesin) – Accessible Active Site, More Amenable Cryptic Binding Site
6.4. Ras (Small G Protein) – Theoretically Druggable, but Difficult in Practice
References
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Chapter 4
Cofactor Chemogenomics
1. Introduction
2. NAD(P)+
2.1. Others NAD(P)+-Dependent Oxidoreductase Targets
3. Riboflavin
4. Tetrahydrofolate
5. Pantothenate
6. Pyridoxal 5¢-Phosphate
7. Thiamin Pyrophosphate
8. Heme
9. S-Adenosyl Methionine
10. Lipoamide, Biotin, and Cobalamin
References
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Chapter 5
Chemogenomics with Protein Secondary-Structure Mimetics
References
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Chapter 6
Database Systems for Knowledge-Based Discovery
1. Introduction
2. Methods
2.1. Reference-Centric Databases
2.2. Molecule-Centric Databases



References
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Chapter 7
Knowledge-Based Virtual Screening: Application to the MDM4/p53 Protein–Protein Interaction
















References
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Chapter 8
Off-Target Networks Derived from Ligand Set Similarity
3.1. Calculating the Parameters of the Reference Database
3.2. Calculating Set-Wise Similarity Ensembles
3.3. Building a Similarity Network
4. Notes
References
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Chapter 9
Chemogenomic Analysis of Safety Profiling Data
1.1. Safety Profiling Data
2.1. Descriptors
2.2. Multicategory Bayesian Models Pipeline Pilot Implementation
3.1. Promiscuity of Compounds – Finding Promiscuous Compounds
3.2. Promiscuity of Compounds –Elucidating “Dirty” Chemical Features
3.3. Assess Promiscuity of Targets
4.1. Principal Component Analysis (PCA) of Chemical Space Similarity
4.2. Venn Diagram of Active Compound Overlaps
4.3. Holistic Data Integration: PCA and Venn Diagrams
4.4. Target Similarity in Chemical Feature Space
4.5. Emergent Information from “Indirect Target Similarity”
4.6. Training Bayesian Models to find Assay Result Differences for Two Targets
References
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Chapter 10
Network and Pathway Analysis of Compound–Protein Interactions
3.1. Metabolite Prediction
3.2. ADMET Properties and Compound–Protein Target Associations
3.2.1. QSAR Modeling
3.3. Structural Similarity Searching
3.4. Functional Analysis
3.4.1. Enrichment Analysis
3.4.2. Network Reconstruction
3.5. Automated Analysis Workflows
3.5.1. Compound Upload and Analysis
3.5.2. Comparing Compound Effects
3.6. Visualizing Data on Maps and Networks
References
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Chapter 11
The Flexible Pocketome Engine for Structural Chemogenomics




















2.2.3. Expected Accuracy of Ligand Docking to a Single Pocket Conformer
2.2.4. Ensemble Docking
2.2.5. Fast Ensemble Docking with a 4D Protocol
2.2.6. Docking Accuracy to Systematic Omission Models
2.3. Scoring Docking Solutions and Compound Screening
2.3.1. Decomposing the Binding Free Energy into Three Components
2.3.2. Measures to Compare Screening Performance
2.3.3. Evaluating Screening Performance of the Pocketome Units
2.4. Tuning the Binding Affinity Estimates for Ligand Specificity Profiling
3. Notes
References
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Chapter 12
Structure-Based Chemogenomics: Analysis of Protein Family Landscapes
2.1. Protein Structure Data
3.1. Mining Databases of Protein 3D Structures
3.2. Exploiting Alignments of Protein Structures – The Ligand Point of View
3.3. Exploiting Alignments of Protein Structures – The Protein Point of View
3.3.1. GRID/CPCA
3.3.2. Variants of GRID/CPCA
References
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Chapter 13
Hypothesis-Driven Screening
References
Jacoby_Index_O
0000960050_O.pdf
Chapter 3
Targeting the Purinome
6.1. Phosphodiesterases – an Accessible, Readily Druggable Active Site
6.2. Protein Kinases – Achieving Selectivity in a Family with High Homology
6.2.1. The Gatekeeper Residue
6.2.2. The XDFG Motif
6.2.3. The Selectivity Region on the aD Helix
6.2.4. The Span of Residues Between the Gatekeeper and the Ribose-Binding Site
6.2.5. Inhibitor-Specific Conformations
6.3. Eg5 (Motor Protein and Mitotic Kinesin) – Accessible Active Site, More Amenable Cryptic Binding Site
6.4. Ras (Small G Protein) – Theoretically Druggable, but Difficult in Practice
References