MEDI 73 |
| Two factors determining the mechanism of in vivo bone antiresorptive activity by nitrogen- containing bisphosphonates (N-BPs) are their ability to target bone mineral (bone affinity) and subsequently, a specific biochemical target within the osteoclast. Thus, once delivered to the bone surface, the N-BPs are taken up by osteoclasts, where they inhibit the enzyme human farnesyl pyrophosphate synthase (hFPPS), disrupting normal cell function. From recently available crystal structures of hFPPS complexed with N-BPs, it has become clear that differences in inhibitor activity at the enzyme level derive from interactions within the geranyl pyrophosphate (GPP) binding site. In particular, the protonated nitrogen in N-BPs forms hydrogen bonds with THR-201 and the carbonyl backbone oxygen of LYS-200. Using AutoDock 3, we modeled enantiomers of a conformationally restricted N-BP, NE-10501 in the GPP site, and found that only the R isomer is competent for the THR-201 and LYS-200 interactions. NE-10501 was synthesized and the crystal structure of its complex with hFPPS was determined, confirming the prediction that the R enantiomer should be stabilized preferentially. Based on this finding, and other considerations, a series of N-BP analogs were designed and docked into the active site of hFPPS. Selected analogs were then synthesized for crystallographic structural studies and bioassay evaluations of hFPPS inhibition. The results indicate that docking studies based on the hFPPS active site structure are usefully predictive in the design of novel N-BP inhibitors for this enzyme.
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Poster Session
7:00 PM-9:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster
Sci-Mix
Division of Medicinal Chemistry |
