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Dr. Youla S. Tsantrizos

Associate Professor
Chemical Biology and Medicinal Chemistry
Chemistry Department
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鈥淚n Silico Design and Parallel Synthesis of Active-Site Inhibitors of the Human Farnesyl Pyrophosphate Synthase鈥�

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The human farnesyl pyrophosphate synthase (hFPPS) is responsible for the catalytic elongation of dimethylallyl pyrophosphate to geranyl pyrophosphate and then to farnesyl pyrophosphate (FPP) via the successive condensation of two isopentenyl pyrophosphate units.听 Post-translational prenylation with FPP of various proteins is crucial to their biological role.听 It is estimated that over 60 human proteins are farnesylated and this modification confers membrane localization, promotes specific protein-protein interactions and plays a critical role in intracellular trafficking and signal transduction.听 Addition of the FPP lipidic moiety to the small GTP-binding proteins Ras is also required in order to regulate the proliferation, invasive properties, and pro-angiogenic activity in human cancers.听 Current therapeutic drugs that inhibit hFPPS (such as risedronate and zoledronate) are used to treat osteoporosis and bone cancer metastasis. A characteristic pharmacophore of all these drugs is a bisphosphonate moiety, which serves as the key anchor in the binding interactions with enzyme.听 However, this structural motif is also responsible for the low oral bioavailability and high accumulation into bone tissue that is observed with this class of compounds.听 Our goal is to design more selective inhibitors with significantly reduced dependency on a bisphosphonate moiety for binding into the active site of hFPPS.听 A structure-based approach has been pursued in designing novel inhibitors of hFPPS, guided by X-ray crystallography and in silico screening using GLIDE庐.听 The development of synthetic methodologies that permit the parallel synthesis of structurally diverse compounds and the biological activity of these compounds will be reported.