Abstract：
Odanacatib (ODN) is a selective cathepsin K inhibitor that acts as an anti-resorptive agent to treat osteoporosis. ODN is also found effective in reducing the effect of severe periodontitis. The interaction between ODN and human serum albumin (HSA) was investigated using spectroscopic, microscopic, and in silico approaches to characterize their binding. The fluorescence intensity of HSA increased upon the addition of increasing concentrations of ODN accompanied by blueshift in the fluorescence spectrum, which suggested hydrophobic formation around the microenvironment of the fluorophores upon ODN binding. A moderate binding affinity was obtained for ODN-HSA binding, with binding constant (Ka) values of ∼104 M-1. Circular dichroism results suggested that the overall secondary and tertiary structures of HSA were both only slightly altered upon ODN binding. The surface morphology of HSA was also affected upon ODN binding, showing aggregate formation. Drug displacement and molecular docking results revealed that ODN preferably binds to site III in subdomain IB of HSA, while molecular dynamics simulations indicated formation of a stable protein complex when site III was occupied by ODN. The ODN-HSA complex was mainly stabilized by a combination of hydrogen bonding, hydrophobic interactions, and van der Waals forces. These findings provide additional information to understand the interaction mechanism of ODN in blood circulation and may help in future improvements on the adverse effects of ODN.
摘要：
Odanacatib（ODN）是一种选择性组织蛋白酶K抑制剂，可作为抗吸收剂治疗骨质疏松症。还发现ODN可有效降低严重牙周炎的影响。ODN与人血清白蛋白(HSA)之间的相互作用用光谱法研究,微观,和计算机模拟方法来表征它们的结合。HSA的荧光强度随着ODN浓度的增加而增加，并伴随着荧光光谱中的蓝移，这表明ODN结合后荧光团微环境周围的疏水形成。对于ODN-HSA结合获得中等结合亲和力,结合常数(Ka)值为104M-1。圆二色性结果表明,HSA的整体二级和三级结构在ODN结合时仅轻微改变。HSA的表面形态也受ODN结合的影响，显示聚集体形成。药物置换和分子对接结果表明，ODN优选与HSA亚结构域IB位点III结合，而分子动力学模拟表明，当位点III被ODN占据时，会形成稳定的蛋白质复合物。ODN-HSA复合物主要通过氢键结合来稳定，疏水相互作用，和范德华部队.这些发现为了解ODN在血液循环中的相互作用机制提供了更多信息，并可能有助于将来改善ODN的不良反应。
