Identification of enoxacin as an inhibitor of osteoclast formation and bone resorption by structure-based virtual screening.
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 D(3), 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.
Ostrov
David A
DA
Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Magis
Andrew T
AT
Wronski
Thomas J
TJ
Chan
Edward K L
EK
Toro
Edgardo J
EJ
Donatelli
Richard E
RE
Sajek
Kristen
K
Haroun
Ireni N
IN
Nagib
Michael I
MI
Piedrahita
Ana
A
Harris
Ashley
A
Holliday
L Shannon
LS
D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D001862:Bone Resorption / Q000473:pathology / Q000517:prevention & control*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015365:Enoxacin / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D051379:Mice; D008958:Models, Molecular; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism
D000199:Actins; D021122:Protein Subunits; D015365:Enoxacin; D025262:Vacuolar Proton-Translocating ATPases