Deprèle Sylvine, Kashemirov Boris A, Hogan James M, Ebetino Frank H, Barnett Bobby L, Evdokimov Artem, McKenna Charles E
Department of Chemistry, University of Southern California, Los Angeles, CA 90089, USA.
Bioorg Med Chem Lett. 2008 May 1;18(9):2878-82. doi: 10.1016/j.bmcl.2008.03.088. Epub 2008 Apr 8.
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(2+), which could contribute to its 100-fold higher IC(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.
从消旋的[6,7-二氢-5H-环戊[c]吡啶-7-基（羟基）亚甲基]双（膦酸）（NE-10501，8）溶液中结晶得到的人法尼基焦磷酸合酶（hFPPS）复合物，该化合物是抗骨质疏松药物利塞膦酸盐的手性类似物，其酶活性位点含有R对映体。通过使用Autodock 3对抑制剂-活性位点相互作用进行计算机建模来评估这种对映体特异性，该软件还在计算hFPPS活性位点中络合的利塞膦酸盐、唑来膦酸盐和米诺膦酸盐的已知构型时评估了预测能力。与这些结构相比，8复合物表现出某些差异，包括仅存在一个Mg(2+)，这可能导致其IC(50)高100倍。描述了8的改进合成方法，该方法将步骤数从12步减少到8步，并使总产率提高了17倍。
