FIGURE SUMMARY
Title

Novel cathepsin K inhibitors block osteoclasts in vitro and increase spinal bone density in zebrafish

Authors
Xue, S.T., Wang, Y.L., Han, X.W., Yi, H., Jiang, W., Si, S.Y., Guo, H.F., Li, Z.R.
Source
Full text @ RSC Adv.
Fig. 1

Structures of Cat K inhibitors.

Fig. 2

Virtual screen found Cat K inhibitor 1x. (a) The 3D model of Cat K inhibitor 14 in docking position (PDB code 4dmy; the picture was prepared with Pymol) in the active site of Cat K and (b) comparison of the docking position of 1q (grey) with 14 (purple) and (c) structures, CDOCKER scores and Cat K IC50s of 14, 1q and 1x.

Fig. 3

Inactive compounds against Cat K.

Fig. 4

Molecular docking calculations of the binding mode of A22 with Cat K (PDB code: 4dmy). (a) and (b) The calculated interactions of A22 (grey) with amino acids (green) in the active pocket of Cat K. (c) Overlay of the crystal structures of Cat L (PDB code: 6ezp), Cat S (PDB code: 4bs5) and Cat B (PDB code: 6ay2) with Cat K. N161 (green) of Cat K located at a loop region where the conformations of the Cat L, S, B and K are different. Compared to the orientation of Y193 (purple) of Cat S, Y67 (green) of Cat K has much less clash with pyridine ring of A22. (d) Backbone carbonyl groups of N161 of Cat K, N286 (purple) of Cat S and D162 (yellow) of Cat L.

Fig. 5

(A) CTX-I detection of test compounds in the bone absorption process; (B) Effects on OC differentiation by test compounds in vitro. Three replicates were tested in each group. **Differences from the control group with probability p < 0.05. ***Differences from the control group with probability p < 0.001. The p value is calculated by Tukey–Kramer multiple comparisons test. The difference is considered statistically significant when probability p value is less than 0.05 and statistically highly significant when probability p value is less than 0.001.

Fig. 6

Binding curves of A20 and A22 dilutions. The affinities (KD) were calibrated with the steady state affinity 1 : 1 binding model using the evaluation software of Biacore 8K.

Fig. 7

Therapeutic effect of A22 in OP zebrafish. (A) Zebrafish spine fluorescence intensity data were collected within the white rectangle area. A22 was administered at a dose of 0.11 μM, 0.33 μM, 1.00 μM, and etidronate disodium (ED) was administered at a dose of 600 μM; (B) spine fluorescence intensity data were calculated based on values obtained from 30 fish each group. (C) A22 therapeutic effect on zebrafish OP. ***Differences from the model group with probability p < 0.001. The p value is calculated using Dunnett's T test and differences with probability p < 0.05 are considered statistically significant.

Acknowledgments
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