Identification of Enoxacin as an Inhibitor of Osteoclast Formation and Bone Resorption by Structure-Based Virtual Screening

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• 作者：David A. Ostrov ; Andrew T. Magis ; Thomas J. Wronski ; Edward K. L. Chan ; Edgardo J. Toro ; Richard E. Donatelli ; Kristen Sajek ; Ireni N. Haroun ; Michael I. Nagib ; Ana Piedrahita ; Ashley Harris ; L. Shanno
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：August 27, 2009
• 年：2009
• 卷：52
• 期：16
• 页码：5144-5151
• 全文大小：1002K
• 年卷期：v.52,no.16(August 27, 2009)
• ISSN：1520-4804

文摘

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.