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      Fluorine in Pharmaceuticals: Looking Beyond Intuition

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      Science

      American Association for the Advancement of Science (AAAS)

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          Abstract

          Fluorine substituents have become a widespread and important drug component, their introduction facilitated by the development of safe and selective fluorinating agents. Organofluorine affects nearly all physical and adsorption, distribution, metabolism, and excretion properties of a lead compound. Its inductive effects are relatively well understood, enhancing bioavailability, for example, by reducing the basicity of neighboring amines. In contrast, exploration of the specific influence of carbon-fluorine single bonds on docking interactions, whether through direct contact with the protein or through stereoelectronic effects on molecular conformation of the drug, has only recently begun. Here, we review experimental progress in this vein and add complementary analysis based on comprehensive searches in the Cambridge Structural Database and the Protein Data Bank.

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          Most cited references 53

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          Interactions with aromatic rings in chemical and biological recognition.

          Intermolecular interactions involving aromatic rings are key processes in both chemical and biological recognition. Their understanding is essential for rational drug design and lead optimization in medicinal chemistry. Different approaches-biological studies, molecular recognition studies with artificial receptors, crystallographic database mining, gas-phase studies, and theoretical calculations-are pursued to generate a profound understanding of the structural and energetic parameters of individual recognition modes involving aromatic rings. This review attempts to combine and summarize the knowledge gained from these investigations. The review focuses mainly on examples with biological relevance since one of its aims it to enhance the knowledge of molecular recognition forces that is essential for drug development.
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            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.
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              Fluorine substituent effects (on bioactivity)

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                Author and article information

                Journal
                Science
                Science
                American Association for the Advancement of Science (AAAS)
                0036-8075
                1095-9203
                September 28 2007
                September 28 2007
                : 317
                : 5846
                : 1881-1886
                Article
                10.1126/science.1131943
                17901324
                © 2007

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