Farnesyl pyrophosphate synthase enantiospecificity with a chiral risedronate analog, [6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl(hydroxy)methylene]bis(phosphonic acid) (NE-10501): Synthetic, structural, and modeling studies
- USC
The complex formed from crystallization of human farnesyl pyrophosphate synthase (hFPPS) from a solution of racemic [6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl(hydroxy)methylene]bis(phosphonic acid) (NE-10501, 8), a chiral analog of the anti-osteoporotic drug risedronate, contained the R enantiomer in the enzyme active site. This enantiospecificity was assessed by computer modeling of inhibitor-active site interactions using Autodock 3, which was also evaluated for predictive ability in calculations of the known configurations of risedronate, zoledronate, and minodronate complexed in the active site of hFPPS. In comparison with these structures, the 8 complex exhibited certain differences, including the presence of only one Mg{sup 2+}, which could contribute to its 100-fold higher IC{sub 50}. An improved synthesis of 8 is described, which decreases the number of steps from 12 to 8 and increases the overall yield by 17-fold.
- Research Organization:
- Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
- Sponsoring Organization:
- USDOE
- OSTI ID:
- 1006771
- Journal Information:
- Bioorg. Med. Chem. Lett., Journal Name: Bioorg. Med. Chem. Lett. Journal Issue: (9) ; 05, 2008 Vol. 18; ISSN 0960-894X
- Country of Publication:
- United States
- Language:
- ENGLISH
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