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Chemogenomics: an emerging strategy for rapid target and drug discovery

Key Points

  • Chemogenomics is the study of the genomic and/or proteomic response of an intact biological system to chemical compounds, or the ability of isolated molecular targets to interact with such compounds.

  • In chemogenomics, large collections of chemical compounds are screened for the parallel identification of biological targets and biologically active compounds.

  • In reverse chemogenomics, gene sequences of interest are expressed as target proteins and screened in a high-throughput, 'target-based' manner by compound libraries. On the basis of the structure–activity relationship homology concept, particular emphasis is placed on the parallel exploration of gene and protein families.

  • In forward chemogenomics, active compounds are identified on the basis of their conditional phenotypic effect on a whole biological system rather than on their inhibition of a specific protein target, followed by the subsequent study of the mechanistic basis of the phenotype.

  • Predictive chemogenomics strategies primarily attempt to holistically characterize gene–compound response associations by concurrently considering the response profiles of thousands of drug responses, coupled with the secondary aim of identifying novel therapeutic molecules.

  • Computational or in silico methods complement experimental chemogenomics strategies in the search for targets and drugs.

  • Chemogenomics has garnered support from virtually all areas of medical research.

  • Cancer research was particularly poised to take advantage of the high-throughput nature of chemogenomics, as the approach can help to identify treatment strategies that selectively target the multiple and complex molecular alterations that are observed in human tumours.

  • Chemogenomics faces unique and mainly technical challenges, including the need for a more refined integration of bioinformatics and chemoinformatics data, a more rational approach to selecting designed compounds from an almost infinite number of synthetic possibilities and the ability to build more focused libraries for screening.

  • A recent trend in chemogenomics focuses on data quality rather than on the number of data points that can be generated.

Abstract

Chemogenomics is an emerging discipline that combines the latest tools of genomics and chemistry and applies them to target and drug discovery. Its strength lies in eliminating the bottleneck that currently occurs in target identification by measuring the broad, conditional effects of chemical libraries on whole biological systems or by screening large chemical libraries quickly and efficiently against selected targets. The hope is that chemogenomics will concurrently identify and validate therapeutic targets and detect drug candidates to rapidly and effectively generate new treatments for many human diseases.

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Figure 1: Forward- and reverse-experimental chemogenomic approaches.
Figure 2: Predictive chemogenomics model.
Figure 3: Relevance network between genome and drug effect.

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Acknowledgements

P. Acklin, H.-J. Roth, P. Schoeffter, A. Schuffenhauer and J. Zimmermann (Novartis) are acknowledged for various support and discussions. M.B. is supported by the Emmy Noether Programme of the Deutsche Forschungsgemeinschaft.

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Correspondence to Markus Bredel.

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DATABASES

NCBI

AP1

ATP citrate lyase

HSP90

FURTHER INFORMATION

Cerep Discovery™

Developmental Therapeutics Program, National Cancer Institute

Eidogen

Iconix Pharmaceuticals DrugMatrix™

Inpharmatica

Kensington InforSense

Protein Data Bank

Scitegic Pipeline pilot

Glossary

TRANSCRIPTIONAL PROFILING

The study of the transcriptome — the complete set of RNA transcripts that are produced by the genome at any one time — using high-throughput methods, such as microarray analysis.

COMBINATORIAL CHEMISTRY

A process for preparing large collections of compounds, or 'combinatorial libraries', by synthesizing all possible combinations of a set of smaller chemical structures or 'building blocks'.

COMPOUND LIBRARY

A structurally diverse collection of chemical molecules, typically containing several hundred thousand entities, that is used to identify new lead candidates.

SYNTHETIC CHEMISTRY

A branch of chemistry that focuses on the deliberate manufacture of pure compounds of defined structure and/or the development of new chemical reactions for this purpose.

CHEMOINFORMATICS

A generic term that encompasses the design, creation, organization, management, retrieval, analysis, dissemination, visualization and use of chemical information, with the intended purpose of guiding drug discovery and development.

FOCUSED LIBRARY

Compound libraries that are enriched for desired properties, such as target-binding affinity, by using computational library design methods.

HIGH-THROUGHPUT SCREENING

The large-scale, trial-and-error evaluation of compounds in a parallel target-based or cell-based assay.

CYTOBLOT

A cellular immunoassay that uses primary antibodies to gauge specific post-translational changes, such as the abundance, modification or conformational change of a protein, as a surrogate measure of a phenotypic change of interest.

AFFINITY MATRIX PURIFICATION

Purification of targets on the basis of their interactions with a ligand that is attached to an immobilized matrix, such as agarose beads, to form an affinity column.

PHAGE DISPLAY

A technique that fuses foreign peptides to capsid proteins on the phage surface. Immobilized libraries of phage-displayed peptides might be screened for binding to specific ligands; determination of the gene sequence of the selected phage identifies the peptide sequence.

PROTEOMIC PROFILING

The systematic analysis of protein expression of normal and diseased tissues that involves the separation, identification and characterization of proteins that are present in a biological sample.

PHYSICOCHEMICAL PROPERTIES

The characteristics of a compound that are relevant to pharmacokinetics studies, such as solubility or membrane permeability.

DRUG-LIKENESS

The concept that drugs share specific molecular properties that distinguish them from other natural or synthetic chemicals.

LEAD OPTIMIZATION

The concurrent optimization of many pharmacological design features, such as target-binding affinity and selectivity, by iterative design, synthesis and testing in biological model systems.

QUANTITATIVE STRUCTURE–ACTIVITY RELATIONSHIP

(QSAR). An analysis that describes the association between the molecular structure of a compound and its ability to affect a biological target.

LIGAND-INDUCED CONFORMATIONAL STABILIZATION

A phenomenon in which substrates, inhibitors, cofactors and even other proteins provide enhanced stability to proteins on binding.

MASS SPECTROMETRY

A technique that is used to determine the composition and abundance of the atoms in and the molecular mass of complex molecules, starting with a small amount of the sample.

[SYNTHETIC] ANALOGUE

Closely related, synthetically synthesized members of a chemotype — a family of molecules that demonstrate a unique core structure or scaffold — with minor chemical modifications that might show improved target-binding affinity and potency compared with the original natural lead compound.

PHARMACOGENOMICS

The study of how and which variations in the human genome affect the response to medications.

ULTRA HIGH-THROUGHPUT SCREENING

Screening activity that is accelerated to more than 100,000 tests per day.

PRIVILEGED STRUCTURE

A core or scaffolding structure that, independent of specific substituents attached to it, imparts a generic activity towards a protein family or a subset of such a family.

DIVERSITY SET [LIBRARY]

Diversity-orientated synthesis-based libraries augment the accessible structural diversity of the library by mimicking the structural complexity and diversity of natural products.

BOOTSTRAP [ANALYSIS]

A type of statistical analysis that is used to test the reliability of certain branches in the evolutionary tree. The bootstrap analysis proceeds by re-sampling the original data, with replacement, to create a series of bootstrap samples of the same size as the original data. The bootstrap value of a node is the percentage of times that a node is present in the set of trees that is constructed from the new data sets.

MYELODYSPLASTIC SYNDROME

One of a group of disorders of the bone marrow that is characterized by the abnormal development of one or more of the cell lines that are normally found in bone marrow, leading to anaemia, abnormally low white blood cell count, tendency to infection and bleeding problems.

DESCRIPTOR

A metric that is used to numerically describe a structure or other molecular attributes of a chemical compound.

RELEVANCE NETWORK ANALYSIS

An analysis technique that is used to find functional genomic clusters by initially linking all genes in a data set by comprehensive pair-wise mutual information and then isolating clusters of genes by removing links that fall under a threshold.

ADMET PROPERTIES [AND MECHANISMS]

The absorption, distribution, metabolism, excretion and toxicity (ADMET) are fundamental pharmacokinetic properties that determine the in vivo efficacy of a drug, together with its intrinsic biological activity on the target.

RECURSIVE PARTITIONING

A process for identifying complex structure–activity relationships in large sets by dividing compounds into a hierarchy of smaller and more homogeneous subgroups on the basis of the statistically most significant descriptor, such as structure fragments.

PHYLOGENETIC-LIKE TREE ALGORITHM

A method for analysing a data set of molecules that assists in identifying chemical classes of interest and sets of molecular features that correlate with a specified biological feature by combining elements of neural nets, genetic algorithms and substructure analysis.

BINARY QUANTITATIVE STRUCTURE–ACTIVITY RELATIONSHIP

A method to assign probabilities of activity to compounds by establishing associations between structural features and molecular properties of these compounds and their biological activities.

PARSING

A process by which programming data is broken into smaller, more distinct chunks of information that can be more easily interpreted and acted on.

INTEGRATION PLATFORMS

A software system that connects different data domains and analysis applications under one graphical user interface.

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Bredel, M., Jacoby, E. Chemogenomics: an emerging strategy for rapid target and drug discovery. Nat Rev Genet 5, 262–275 (2004). https://doi.org/10.1038/nrg1317

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