Selective and orally bioavailable phenylglycine tissue factor/factor VIIa inhibitors.

We describe the structure-based design and synthesis of highly potent, orally bioavailable tissue factor/factor VIIa inhibitors which interfere with the coagulation cascade by selective inhibition of the extrinsic pathway.

Fluorine in medicinal chemistry.

Fluorinated compounds are synthesized in pharmaceutical research on a routine basis and many marketed compounds contain fluorine. The present review summarizes some of the most frequently employed strategies for using fluorine substituents in medicinal chemistry. Quite often, fluorine is introduced to improve the metabolic stability by blocking metabolically labile sites. However, fluorine can also be used to modulate the physicochemical properties, such as lipophilicity or basicity. It may exert a substantial effect on the conformation of a molecule. Increasingly, fluorine is used to enhance the binding affinity to the target protein. Recent 3D-structure determinations of protein complexes with bound fluorinated ligands have led to an improved understanding of the nonbonding protein-ligand interactions that involve fluorine.

Scaffold hopping.

The aim of scaffold hopping is to discover structurally novel compounds starting from known active compounds by modifying the central core structure of the molecule. Scaffold hopping is a central task of modern medicinal chemistry requiring a multitude of techniques, which are discussed in this article. Their application has led to several molecules with chemically completely different core structures, and yet binding to the same receptor. Computational approaches for scaffold hopping highlight the challenges of the field that are still unsolved.:

Hit and lead generation: beyond high-throughput screening.

The identification of small-molecule modulators of protein function, and the process of transforming these into high-content lead series, are key activities in modern drug discovery. The decisions taken during this process have far-reaching consequences for success later in lead optimization and even more crucially in clinical development. Recently, there has been an increased focus on these activities due to escalating downstream costs resulting from high clinical failure rates. In addition, the vast emerging opportunities from efforts in functional genomics and proteomics demands a departure from the linear process of identification, evaluation and refinement activities towards a more integrated parallel process. This calls for flexible, fast and cost-effective strategies to meet the demands of producing high-content lead series with improved prospects for clinical success.

Virtual screening and fast automated docking methods.

Recent advances in high-throughput protein structure determination and in computational chemistry have refocused attention on virtual screening and fast automated docking methods. This review provides a brief introduction to the basic ideas and outlines computational tools currently used. We also provide several examples of where virtual screening has proved successful, highlighting the usefulness of the approach.