Chemogenomics
Chemogenomics, or chemical genomics, is the systematic
A common method to construct a targeted chemical library is to include known ligands of at least one and preferably several members of the target family. Since a portion of ligands that were designed and synthesized to bind to one family member will also bind to additional family members, the compounds contained in a targeted chemical library should collectively bind to a high percentage of the target family.[3]
Strategy
Chemogenomics integrates target and drug discovery by using active compounds, which function as ligands, as probes to characterize proteome functions. The interaction between a small compound and a protein induces a phenotype. Once the phenotype is characterized, we could associate a protein to a molecular event. Compared with genetics, chemogenomics techniques are able to modify the function of a protein rather than the gene. Also, chemogenomics is able to observe the interaction as well as reversibility in real-time. For example, the modification of a phenotype can be observed only after addition of a specific compound and can be interrupted after its withdrawal from the medium.
Currently, there are two experimental chemogenomic approaches: forward (classical) chemogenomics and reverse chemogenomics. Forward chemogenomics attempt to identify drug targets by searching for molecules which give a certain phenotype on cells or animals, while reverse chemogenomics aim to validate phenotypes by searching for molecules that interact specifically with a given protein.[4] Both of these approaches require a suitable collection of compounds and an appropriate model system for screening the compounds and looking for the parallel identification of biological targets and biologically active compounds. The biologically active compounds that are discovered through forward or reverse chemogenomics approaches are known as modulators because they bind to and modulate specific molecular targets, thus they could be used as ‘targeted therapeutics’.[1]
Forward chemogenomics
In forward chemogenomics, which is also known as classical chemogenomics, a particular phenotype is studied and small compound interacting with this function are identified. The molecular basis of this desired phenotype is unknown. Once the modulators have been identified, they will be used as tools to look for the protein responsible for the phenotype. For example, a loss-of-function phenotype could be an arrest of tumor growth. Once compounds that lead to a target phenotype have been identified, identifying the gene and protein targets should be the next step.[5] The main challenge of forward chemogenomics strategy lies in designing phenotypic assays that lead immediately from screening to target identification.
Reverse chemogenomics
In reverse chemogenomics, small compounds that perturb the function of an enzyme in the context of an in vitro enzymatic test will be identified. Once the modulators have been identified, the phenotype induced by the molecule is analyzed in a test on cells or on whole organisms. This method will identify or confirm the role of the enzyme in the biological response.[5] Reverse chemogenomics used to be virtually identical to the target-based approaches that have been applied in drug discovery and molecular pharmacology over the past decade. This strategy is now enhanced by parallel screening and by the ability to perform lead optimization on many targets that belong to one target family.
Applications
Determining mode of action
Chemogenomics has been used to identify
Beyond TCM and Ayurveda, chemogenomics can be applied early in drug discovery to determine a compound's mechanism of action and take advantage of genomic biomarkers of toxicity and efficacy for application to Phase I and II clinical trials.[7]
Identifying new drug targets
Chemogenomics profiling can be used to identify totally new therapeutic targets, for example new antibacterial agents.
Identifying genes in biological pathway
Thirty years after the posttranslationally modified histidine derivative
See also
- Chemical biology
- Chemical genetics
- Drug discovery
- High-throughput screening
- Personalized medicine
- Phenotypic screening
References
- ^ S2CID 11952369.
- .
- PMID 11470611.
- ^ Ambroise Y. "Chemogenomic techniques". Archived from the original on 23 August 2013. Retrieved 28 July 2013.
- ^ PMID 18346803.
- PMID 23351136.
- PMID 15335294.
- PMID 23676922.
- PMID 22928710.
Further reading
- Folkers G, Kubinyi H, Müller G, Mannhold R (2004). Chemogenomics in drug discovery: a medicinal chemistry perspective. Weinheim: Wiley-VCH. ISBN 978-3-527-30987-0.
- Jacoby E (2009). Chemogenomics: methods and applications. Totowa, NJ: Humana Press. ISBN 978-1-60761-273-5.
- Weill N (2011). "Chemogenomic approaches for the exploration of GPCR space". Current Topics in Medicinal Chemistry. 11 (15): 1944–55. PMID 21470168.
External links
- GLASS: A comprehensive database for experimentally-validated GPCR-ligand associations
- Kubinyi's slides