Inhibition of Geranylgeranyl Diphosphate Synthase by Bisphosphonates: A Crystallographic and Computational Investigation

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• 作者：Cammy K.-M. Chen ; Michael P. Hudock ; Yonghui Zhang ; Rey-Ting Guo ; Rong Cao ; Joo Hwan No ; Po-Huang Liang ; Tzu-Ping Ko ; Tao-Hsin Chang ; Shiou-chi Chang ; Yongcheng Song ; Jordan Axelson ; Anup Kumar ; Andre
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：September 25, 2008
• 年：2008
• 卷：51
• 期：18
• 页码：5594-5607
• 全文大小：536K
• 年卷期：v.51,no.18(September 25, 2008)
• ISSN：1520-4804

文摘

We report the X-ray structures of several bisphosphonate inhibitors of geranylgeranyl diphosphate synthase, a target for anticancer drugs. Bisphosphonates containing unbranched side chains bind to either the farnesyl diphosphate (FPP) substrate site, the geranylgeranyl diphosphate (GGPP) product site, and in one case, both sites, with the bisphosphonate moiety interacting with 3 Mg²⁺ that occupy the same position as found in FPP synthase. However, each of three “V-shaped” bisphosphonates bind to both the FPP and GGPP sites. Using the Glide program, we reproduced the binding modes of 10 bisphosphonates with an rms error of 1.3 Å. Activities of the bisphosphonates in GGPPS inhibition were predicted with an overall error of 2× by using a comparative molecular similarity analysis based on a docked-structure alignment. These results show that some GGPPS inhibitors can occupy both substrate and product site and that binding modes as well as activity can be accurately predicted, facilitating the further development of GGPPS inhibitors as anticancer agents.