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W. J. Geldenhuys, J. Sapitro, M. Celmer, H. Nakamura; 3D-QSAR and Docking Studies of the Activin Receptor-Like Kinase 5 Antagonists for Use in Glaucoma Filtration Surgery. Invest. Ophthalmol. Vis. Sci. 2010;51(13):701.
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TGF-β activity has been implicated in ocular scarring in the eyes, including that following glaucoma filtration surgery.The development of kinase inhibitors for activin receptor-like kinase (ALK) 5 (also known as TGF-β receptor type I) is therapeutically important. The purpose of our study was to determine 3D-quantitiative structure-activity relationship (QSAR) between ALK-5 and its inhibitors.
For the 3D-QSAR, we used a comparative molecular field analysis (CoMFA) model. The ALK-5 inhibitor SB-505124 was used as template molecule for the alignment of the compounds.
To train the CoMFA model, 17 previously published compounds where used and the resulted partial least squares cross-validated statistical model yielded a model with q2> 0.3. This model was tested with a small test set of 4 compounds to see how well it would be able to predict inhibition (pIC50) of the ALK-5 inhibitors. The CoMFA model correctly predicted the experimental inhibition of the kinase inhibitors correctly more than 90% of the time. Furthermore, docking studies successfully showed where the important hydrogen-bonds which are important for ALK-5 binding by these kinase inhibitors.
These results from the CoMFA models could enable the development of novel inhibitors which can be used in the treatment of glaucoma filtration surgery
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