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Chemogenomics is a new strategy in drug discovery which, in principle, 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 investigation 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 ligands. The term “privileged structures” has been defined for scaffolds, such as the benzodiazepines, which very often produce biologically active analogs in a target 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.

Targeting protein superfamilies via chemogenomics is based on a similarity clustering of gene sequences and molecular structures of ligands. Both target and ligand clusters are linked by generating binding affinity profiles of chemotypes vs a target panel. The application of this multidimensional similarity paradigm will be described in the context of Lead Generation to identify novel chemical hit classes for G-protein coupled receptors.

G-protein coupled receptors (GPCRs) are promising targets for the discovery of novel drugs. In order to identify novel chemical series, high-throughput screening (HTS) is often complemented by rational chemogenomics lead finding approaches. We have compiled a GPCR directed screening set by ligand-based virtual screening of our corporate compound database. This set of compounds is supplemented with novel libraries synthesized around proprietary scaffolds. These target-directed libraries are designed using the knowledge of privileged fragments and pharmacophores to address specific GPCR subfamilies (e. g., purinergic or chemokine-binding GPCRs). Experimental testing of the GPCR collection has provided novel chemical series for several GPCR targets including the adenosine A1, the P2Y_12, and the chemokine CCR1 receptor. In addition, GPCR sequence motifs linked to the recognition of GPCR ligands (termed chemoprints) are identified using homology modeling, molecular docking, and experimental profiling. These chemoprints can support the design and synthesis of compound libraries tailor-made for a novel GPCR target.

This article covers the diversity-oriented synthesis (DOS) of small molecules in order to generate a collection of pure compounds that are attractive for lead generation in a phenotypic, high-throughput screening approach useful for chemical genetics and drug discovery programmes. Nature synthesizes a rich structural diversity of small molecules, however, unfortunately, there are some disadvantages with using natural product sources for diverse small-molecule discovery. Nevertheless we have a lot to learn from nature. The efficient chemical synthesis of structural diversity (and complexity) is the aim of DOS. Highlights of this article include a discussion of nature’s and synthetic chemists’ strategies to obtain structural diversity and an analysis of molecular descriptors used to classify compounds. The assessment of how successful one diversity-oriented synthesis is vs another is subjective; therefore we use freely available software (www.cheminformatics.org/diversity) to assess structural diversity in any combinatorial synthesis.

The interface of chemistry and biology offers many opportunities to explore different aspects of cell biology. The emerging field of chemical genetics is providing the chemical means to understand biological systems not easily accessible using classical genetic manipulations. In this article, we will discuss how natural product mode of action studies and novel bio-organic manipulation of intracellular protein levels are proving useful in the exploration of cell biology.

The nuclear receptors are ideal targets to control the expression of specific genes with small molecules. Estrogen receptor can activate or repress transcription though a number of different pathways. As part of an effort to develop reagents that selectively target specific transcriptional regulatory pathways, analogs of 4-hydroxytamoxifen were synthesized with variations in the basic side chain. In vitro binding assays and cell-based luciferase reporter gene assays confirm that all the derivatives have high affinity for the receptor and high potency at repressing direct estrogen receptor-mediated transcription.

The majority of all proteins are modularly built from a limited set of approximately 1,000 structural domains. The knowledge of a common protein fold topology in the ligand-sensing cores of protein domains can be exploited for the design of small-molecule libraries in the development of inhibitors and ligands. Thus, a novel strategy of clustering protein domain cores based exclusively on structure similarity considerations (protein structure similarity clustering, PSSC) has been successfully applied to the development of small-molecule inhibitors of acetylcholinesterase and the 11β-hydroxysteroid dehydrogenases based on the structure of a naturally occurring Cdc25 inhibitor. The efficiency of making use of the scaffolds of natural products as biologically prevalidated starting points for the design of compound libraries is further highlighted by the development of benzopyran-based FXR ligands.

Drug discovery in the chemogenomic space has seen some tremendous changes over the last decade. Compared to previous times, not only the number of available chemical compounds for screening, but also the number of molecular targets used for screening has increased significantly. This has triggered the need for very fast, efficient, and effective novel readout technologies for compound testing. Novartis has developed two novel high-throughput screening (HTS) technologies for that purpose — NanoScreen and SpeedScreen. NanoScreen is a highly miniaturized and fully automated HTS/uHTS test system with confocal single-molecule as well as non-confocal detection capabilities and is used for functional screening in the range of 1–5 µl per sample. The integration of the single-molecule readout technologies into the system enables highly sophisticated biochemical test systems with multi-parameter readout for very high data quality. SpeedScreen is a highly miniaturized and automated screening system for high-throughput affinity-selection of compounds. In practice, pools of compounds are incubated with the target protein and the unbound chemical compounds are removed from the target-compound complex via very fast, multiparallel size-exclusion-chromatography. The holoenzyme is disintegrated and analyzed via microbore reversed-phase high performance liquid chromatography (microbore RP-HPLC). Both systems have been developed and implemented with great success at the Novartis Lead Discovery Center (LDC) in Basel. These technologies have enabled us to access targets that would otherwise not have been possible, e.g., very expensive targets, “orphan” drug targets, or targets that are “non-tractable” by conventional screening technologies. Taken together, these novel screening technologies enable novel approaches for chemogenomic research that would have not been possible in the past.