Identification of enoxacin as an inhibitor of osteoclast formation and bone resorption by structure-based virtual screening.
Identification of enoxacin as an inhibitor of osteoclast formation and bone resorption by structure-based virtual screening.
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DOI：
10.1021/jm900277z
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发表时间：
2009-08-27
影响因子：
7.3
通讯作者：
Holliday LS
中科院分区：
文献类型：
--
作者：
Ostrov DA;Magis AT;Wronski TJ;Chan EK;Toro EJ;Donatelli RE;Sajek K;Haroun IN;Nagib MI;Piedrahita A;Harris A;Holliday LS
破骨细胞的骨吸收需要液泡H+-ATP酶（V-ATP酶）的B2亚基与微丝之间的相互作用。B2上的肌动蛋白结合位点的原子同源性模型的产生和分子对接模拟进行。依诺沙星，一种氟喹诺酮类抗生素，被确定，并在体外试验表明，依诺沙星阻断纯化的B2和微丝之间的结合。依诺沙星剂量依赖性地减少了在用1，25-二羟维生素D3刺激的小鼠骨髓培养物中分化的破骨细胞的数量，以及破骨细胞活性的标志物和骨切片上形成的吸收陷窝的数量。依诺沙星抑制破骨细胞的形成浓度，而成骨细胞的形成没有改变。总之，依诺沙星是一种新型的破骨细胞骨吸收的小分子抑制剂，其通过独特的机制起作用，因此是开发新型抗骨吸收剂的有吸引力的先导分子。
An interaction between the B2 subunit of vacuolar H+-ATPase (V-ATPase) and microfilaments is required for osteoclast bone resorption. An atomic homology model of the actin binding site on B2 was generated and molecular docking simulations were performed. Enoxacin, a fluoroquinolone antibiotic, was identified and in vitro testing demonstrated that enoxacin blocked binding between purified B2 and microfilaments. Enoxacin dose dependently reduced the number of osteoclasts differentiating in mouse marrow cultures stimulated with 1,25-dihydroxyvitamin D3, as well as markers of osteoclast activity, and the number of resorption lacunae formed on bone slices. Enoxacin inhibited osteoclast formation at concentrations where osteoblast formation was not altered. In summary, enoxacin is a novel small molecule inhibitor of osteoclast bone resorption that acts by an unique mechanism and is therefore an attractive lead molecule for the development of a new class of antiosteoclastic agents.
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DOI：
10.1097/spc.0b013e32830baac2
发表时间：
2008-09-01
影响因子：
2.1
作者：
Lipton, Allan;Jun, Susie
通讯作者：
Jun, Susie
影响因子：
4.8
作者：
Lee, BS;Gluck, SL;Holliday, LS
通讯作者：
Holliday, LS
影响因子：
4.8
作者：
HOLLIDAY, LS;DEAN, AD;GLUCK, SL
通讯作者：
GLUCK, SL
影响因子：
4.8
作者：
Holliday, LS;Welgus, HG;Gluck, SL
通讯作者：
Gluck, SL
影响因子：
3.3
作者：
Rubinstein, E
通讯作者：
Rubinstein, E