Toward a hierarchical virtual screening and toxicity risk analysis for identifying novel CA XII inhibitors.

Carbonic anhydrase isoform XII (CA XII) is a potential target for cancer treatment. In this study, pharmacophore modeling, hierarchical virtual screening, and toxicity risk analysis were performed for identifying novel CA XII inhibitors. A pharmacophore model of two classes of CA XII inhibitors was generated. The pharmacophore model indicated the important features of inhibitors for the binding with the CA XII. The model was then utilized to screen the ZINC and CoCoCo databases for retrieving potential hit compounds of CA XII. For accurate conclusions about the selectivity of inhibitors, the retrieved molecules which obey of Lipinski's rule of five (RO5) and have no toxicity risk were docked in a CA XII 3D structure by smina. Finally, on the basis of binding affinity and the binding mode of the molecules, twelve molecules were prioritized as promising hits. It should be noted that two of hits H5 and H6 were previously reported in the CHEMBL database. This hierarchical method is worthy of reducing the time and using almost all information available. The final hits may be used as a lead to discovery novel CA XII inhibitors.