Chemogenomics

The completion of the human genome project has provided an abundance of potential targets for therapeutic intervention.

[5] The main challenge of forward chemogenomics strategy lies in designing phenotypic assays that lead immediately from screening to target identification.

In reverse chemogenomics, small compounds that perturb the function of an enzyme in the context of an in vitro enzymatic test will be identified.

[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.

Therapeutic actions (or phenotypes) for that class include anti-inflammatory, antioxidant, neuroprotective, hypoglycemic activity, immunomodulatory, antimetastatic, and hypotensive.

Sodium-glucose transport proteins and PTP1B (an insulin signaling regulator) were identified as targets which link to the hypoglycemic phenotype suggested.

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.

[8] The study capitalized on the availability of an existing ligand library for an enzyme called murD that is used in the peptidoglycan synthesis pathway.

Ligands identified would be expected to be broad-spectrum Gram-negative inhibitors in experimental assays since peptidoglycan synthesis is exclusive to bacteria.

Thirty years after the posttranslationally modified histidine derivative diphthamide was determined, chemogenomics was used to discover the enzyme responsible for the final step in its synthesis.