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Chemogenomics aims towards the systematic identification of small molecules that interact with the products of the genome and modulate their biological function. This Opinion article summarizes the different knowledge-based chemogenomics strategies that are followed and outlines the challenges and opportunities that will impact drug discovery. Chemogenomics aims towards the systematic identification of small molecules that interact with the products of the genome and modulate their biological function. While historically the approach is based on efforts that systematically explore target gene families like kinases, today additional knowledge-based systematization principles are followed within early drug discovery projects which aim to biologically validate the targets and to identify starting points for chemical lead optimization. While the expectations of chemogenomics are very high, the reality of drug discovery is quite sobering with very high project attrition rates. This article summarizes the different knowledge-based chemogenomics strategies that are followed and outlines the challenges and potential opportunities that will impact drug discovery.

The NIBR (Novartis Institutes for BioMedical Research) compound collection enrichment and enhancement project integrates corporate internal combinatorial compound synthesis and external compound acquisition activities in order to build up a comprehensive screening collection for a modern drug discovery organization. The main purpose of the screening collection is to supply the Novartis drug discovery pipeline with hit-to-lead compounds for today's and the future's portfolio of drug discovery programs, and to provide tool compounds for the chemogenomics investigation of novel biological pathways and circuits. As such, it integrates designed focused and diversity-based compound sets from the synthetic and natural paradigms able to cope with druggable and currently deemed undruggable targets and molecular interaction modes. Herein, we will summarize together with new trends published in the literature, scientific challenges faced and key approaches taken at NIBR to match the chemical and biological spaces.

In the postgenomic age of drug discovery, targets can no longer be viewed as singular objects having no relationship to one another. All targets are now visible and the systematic exploration of selected target families appears to be a promising way to speed up and further industrialize target-based drug discovery. Chemogenomics refers to such systematic exploration of target families and aims to identify all possible ligands of all target families. Because biology works by applying prior knowledge to an unknown entity, chemogenomics approaches are expected to be especially effective within the previously well-explored target families, for which, in addition to the protein sequence and structure information, considerable knowledge of pharmacologically active structural classes and structure-activity relationships exists. For the new target families, chemical knowledge will have to be generated and beyond biological target validation, the emphasis is on chemistry to provide the molecules with which their novel biology and pharmacology can be studied. Using examples from the previously most successfully explored target families, the GPCR family in particular, we summarize herein our current chemogenomics knowledge-based strategies for drug discovery, which are founded on the high integration of chem and bioinformatics, thereby providing a molecular informatics frame for the exploration of the new target families., ((c) 2003 Prous Science. All rights reserved.)