Solving Drug Discovery with Metabolomics and Metabonomics: New Aspects of the “Omic” Revolution

Published by: Drug and Market Development Publishing

Published: Feb. 1, 2005 - 245 Pages

Table of Contents

Chapter 1: Executive Summary



Chapter 2: Definitions and Models

Metabolomics and Metabonomics

Metabonome Provides Real-World Information about Drug Toxicity, Gene Function, and Homeostasis

The Metabolome

Utility of the Metabolome and Metabolic Toxicology in Drug Discovery

Beyond the Genome and the Proteome

Metabonomic Intervention in the Drug Development Pipeline

Glucoronidation and Metabonates

The Complexity of Metabolome

Metabolomics and Plants

Metabonomics Needs Biologists, Computer Scientists, Chemists, Engineers, Mathematicians, and Physicists

Systems Biology

Metabolic Control Analysis (MCA)

Historical Genesis of MCA

Biochemical Considerations

Mammal-Microbe-Xenobiotic Systems’ Interactions

Gut Metabolic System

Pattern Recognition Methodologies

Global Metabolomic Analysis-Metabolomic Vector Analysis

Predictive and Preventive Medicine

Related “Omic” Disciplines and Drug Discovery Platforms

Genomics and Transcriptomics

Lipomics and Glycomics

The Immunome

References

Chapter 3: Bioinformatics-Databases and Software

Databases for Metabolic Pathway Analysis

Introduction to Pathway Analysis

Bibliome

Data Mining

Information Technology in Life Sciences

Bioinformatics in Molecular R&D

Predicting Gene Function and Structure

DNA Technologies

Intranet and Internet

Gene Mapping and Genome Sequencing

Automation and Computerization of Biotech Research

Algorithms

Chemometrics

University of Minnesota Biocatalysis/Biodegradation Database (UM-BBD)

Leading Database Resources

PathDB Depiction

Selective Target Evaluation in Microbes (STEM™)

PseudoCyc, a Pathway/Genome Database for Pseudomonas Aeruginosa and MetaCyc Database

Biomolecular Interaction Network Database (BIND)

123genomics

GGOBI

Plant Systems

Platform Plant Metabolomics (PPM)

Arabidopsis

Medicago Trunculata

International Rice Research Institute (IRRI)

Natural Product Analysis

Max Planck Institute (MPI) for Molecular Plant Physiology

Databases Associated with Genomics and Proteomics

National Center for Biological Information (NCBI)

Databases and Software

NCBI’s Nucleotide and Genomic Database

European Bioinformatics Institute, and the Wellcome Trust Genome

ExPASy Molecular Biology Server

Boehringer Mannheim Biochemical Pathways

Biocarta’s Proteomic Pathway Project

Structural Classification of Proteins (SCOP)

Protein Function and Biochemical Pathways (PFBP) Project

BRENDA

Software for Metabolic Pathway Analysis

Computer Simulation of Metabolism

Compound, Organism, Reaction and Enzyme (CORE)

Artificial Neural Nets (ANN)

Quantification of Biotechnological Systems

The GO Consortium

FlyBase

CellML and E-Cell

E-Cell Project

References

On the representation of gene function in genetic databases

Chapter 4: Techniques in Metabolomics and Metabonomics

Analytical Techniques

Overview of Spectroscopic Techniques

Mass Spectrometry (MS)

FTIR Spectroscopy

Diffuse Reflectance-Absorbance FT-IR

Dispersive Raman Spectroscopy

Atomic Absorption Spectrophotometry

Pyrolysis Mass Spectrometry

Combination Strategies Including: GC/MS, FTIR-MS, Liquid Chromatography (LC)/MS, and LC/MS/MS

Evaluation of Glycosylation Sites by MS/MS

MS/MS Analysis Used For Flavonoid Identification and Determination

High Throughput Screening (HTS) LC-MS

Analysis of Fingerprinting Methods

Use of NMR in Biomedicine

LC/NMR

Gas Chromatography (GC)

High Performance Liquid Chromatography (HPLC)

Lab-on-a-Chip

Capillary Electrophoresis (CE)/MS of Plants

Recent Examples of Drug Enantioseparations by Chiral CE

Conclusions Technological overview of Spectroscopic Methodologies

Chapter 5: Metabolomics and Metabonomics: Markets, Applications, and Current Research

Market Value

Innovative Enhancements to the MS Technologies

2D Gels

Mass Spectroscopy

SWOT Analysis for Metabolomic Technologies

Applications and Research

Main Metabolomic and Metabonomic Application Categories

Unifying Research in Genomics and Proteomics

Drug Discovery and Development

Genomics to Metabolomics

Metabolite Profiling Defines Metabotypes

Bioarray Innovations

Integrated Genomics

Third Generation Proteomics

Target Identification and Diagnostic Biomarkers

Clinical End Point and Presence of Biomarker

Target Validation

Lead Prioritization

Preclinical and Clinical Studies

Metabolomic Analyses to Assist With Toxicity Profiles

Personalized Medicine and Nutrition

Current Research on Pathway Analysis

Future Directions

Chapter 6: Company Profiles

Taxicogenomics-Icora (formerly Paradigm Genetics), Morphochem Inc

Chemogenomics-Acadia Pharmaceuticals, Amorpha Discovery Corp, Neogenesis Pharmaceuticals, Vertex Pharmaceuticals

Ribonomics-Biolog, Intradigm Corp., Ribonomics Inc, Sequitur

Phenomics-Mitokor Inc, Cellular Genomics Inc, Phenomenome Discoveries Inc, Organon

Target Identification-Metabolon Inc, High Chem Ltd., Metabometrix, GeneGo

COMET Network, Vion Pharmaceuticals, Pfizer

PhysioLab Entelos

Acadia Pharmaceuticals

Accelyrs Inc

Agilent Technologies, Inc

Bruker BioSciences Corp

Caliper Life Sciences

Icoria, Inc. (Paradigm Genetics)

Sequenom

TABLE OF EXHIBITS

Exhibit 2.1 The Omics Industry

Exhibit 2.2 Roche’s Chemical Pathways Chart

Exhibit 2.3 Complexity of the Metabolome

Exhibit 2.4 Characteristic Metabolomics Signature Spectra

Exhibit 2.5 Principle Component Analysis of Two Phenotypes: Correlation of Proteome to Metabolome

Exhibit 2.6 Mammal-Microbe-Xenobiotic Systems’ Interactions

Exhibit 2.7 Sequence of Major Endogenous and Sym-xenobiotic after Colonization of Gut Microfloral Constituencies

Exhibit 2.8 Pachinko Metabolism Model

Exhibit 2.9 Metabolic Vector Analysis

Exhibit 2.10 Epigenetic Feedback Control of Protein Expression and Metabolic Profiles

Exhibit 2.11 Network Array Demonstrating the Connectivity of the Proteome to Metabolic Energy

Exhibit 2.12 Lipomics: Early Biochemical Steps of Cholesterol Synthesis

Exhibit 2.13 Galactose Metabolic System (“Glycome”)

Exhibit 2.14 Pearson Correlation Map of Metabolites

Exhibit 3.1 Screen View of KEGG Start Up

Exhibit 3.2 Fatty Acid Metabolism

Exhibit 3.3 Pathways Determined by UM-BBD Databases

Exhibit 3.4 Compounds and Reactions Page for the (+)-Camphor Pathway

Exhibit 3.5 Pathway of Cyanuric Acid Degradation

Exhibit 3.6 PathDB Software Depiction

Exhibit 4.1 Schematics of Commonly Used Metabolomic Techniques

Exhibit 4.2 Desorption/Ionization On Porous Silicon Mass Spectroscopy

Exhibit 4.3 MS Spectra for Separate HPLC Peaks of MeTFMA Metabolites

Exhibit 4.4 Glycosylation Mapping by CE/MS Data

Exhibit 4.5 MS/MS Fingerprinting

Exhibit 4.6 Characteristic Mass Spectra of Fatty Acids

Exhibit 4.7 HTS LC-MS Column and Solvent Selection Valves

Exhibit 4.8 NMR Techniques in Biomedicine

Exhibit 4.9 E. coli Peptides Analyzed by 2DGE-LC-MS

Exhibit 4.10 Chinese Herbal Preparation Extracts

Exhibit 4.11 Drug Enantiomer Chiral Selection after CE

Exhibit 5.1 Market Forecast of Bio Tools

Exhibit 5.2 SWOT analysis for Metabolomic Industries

Exhibit 5.3 From Genome to Metabolome

Exhibit 5.4 Human Metabolome Profile

Exhibit 5.5 The Interplay of the Metabolome and the Genome

Exhibit 5.6 1H NMR Spectra of Different Rat Tissues

Exhibit 6.1 Metabolomic Profiles in Drug Discovery

Exhibit 6.2 Mass Distribution of Metabolomic Products

Exhibit 6.3 Metabolomic Comparison of Control (upper panel) and Autistic Children Plasma

Exhibit 6.4 NADH Biosynthetic Pathway

Exhibit 6.5 Network Around Drug-metabolizing Enzyme CYP3A4

Exhibit 6.6 From NCE to Pathways

Abstract

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