Chemogenomics
From DrugPedia: A Wikipedia for Drug discovery
Chemogenomics can be defined as the study of genomic responses to chemical compounds. The goal is the rapid identification of novel drugs and drug targets embracing multiple early phase drug discovery technologies ranging from target identification and validation, over compound design and chemical synthesis to biological testing and ADME profiling.
[edit] Introduction
Chemical biology, chemical genetics, and chemogenomics are recent strategies in drug discovery. Although definitions in the literature are somehow diffuse and inconsistent, a differentiation of the terms will be attempted here: Chemical biology may be defined as the study of biological systems, e.g., whole cells, under the influence of chemical libraries. If a new phenotype is discovered by the action of a certain substance, the next step is the identification of the responsible target. Chemical genetics is the dedicated study of protein function, e.g., signaling chains, under the influence of ligands which bind to certain proteins or interfere with protein–protein interaction; sometimes orthog- onalligand–proteinpairsaregeneratedtoachieveselectivityforacertain protein. Chemogenomics defines, in principle, the screening of the chemi- cal universe, i.e., all possible chemical compounds, against the target universe, i.e., all proteins and other potential drug targets. Whereas this task can never be achieved, due to the almost infinite size of the chemical universe, the systematic screening of libraries of congeneric compounds against members of a target family offers unprecedented chances in the search for compounds with significant target or subtype specificity.
Chemogenomics is a new strategy in drug discovery which, in princi- ple, searches for all molecules that are capable of interacting with any biological target. Because of the almost infinite number of drug-like organic molecules, this is an impossible task. Therefore chemogenomics has been defined as the investi- gation of classes of compounds (libraries) against families of functionally related proteins. In this definition, chemogenomics deals with the systematic analysis of chemical–biological interactions. Congeneric series of chemical analogs are probes to investigate their action on specific target classes, e.g., GPCRs, kinases, phosphodiesterases, ion channels, serine proteases, and others. Whereas such a strategy developed in pharmaceutical industry almost 20 years ago, it is now more systematically applied in the search for target- and subtype-specific lig- ands. The term “privileged structures” has been defined for scaffolds, such as the benzodiazepines, which very often produce biologically active analogs in a tar- get family, in this case in the class of G-protein-coupled receptors. The SOSA approach is a strategy to modify the selectivity of biologically active compounds, generating new drug candidates from the side activities of therapeutically used drugs.
[edit] Chemical Genetics
Classical genetics sets a (random) mutation, e.g., by irradiation, and tries to conclude from a new phenotype to the genotype. “Chemical genetics” is another new term for a strategy that has also been used since long ago, in a less systematic manner; it describes the purposeful investiga- tion of proteins by small molecules or libraries, for target identification (forwardchemical genetics) ortarget validation (reversechemical genet- ics). Sometimes, orthogonal ligand-receptorpairs are constructed if selective ligands are not available. Selective ki-nase inhibition has been achieved by specifically converting nonspecific, low-affinity inhibitors into larger analogs and to construct certain kinase mutants that specifically accommodate these originally less well-fitting ligands by their larger binding pocket. In this manner, the specific inhibition of a certain kinase can be studied without having developed an inhibitor of comparable specificity against the wild-type kinase.
