Investigating the potential activity of carbonic anhydrase IX agents against cancer by moleculardocking simulation

Investigating the potential activity of carbonic anhydrase IX agents against cancer by moleculardocking simulation
Rahman Abdizadeh,^1,* Tooba Abdizadeh,²
1. Department of Medical Parasitology and Mycology, Faculty ofMedicine, Shahrekord University of Medical Sciences,Shahrekord, Iran
2. Clinical Biochemistry Research Center, Basic Health SciencesInstitute, Sharekord University of Medical Sciences,Shahrekord, Iran
Introduction: Carbonic anhydrase IX (CA IX) is a trans membrane protein that highly expressed in hypoxia tumor cells. Inhibition of CA IX isoenzyme by small molecule CA inhibitors such as sulfonamide derivatives has blocked tumor growth in multiple cancer models and CA IX is a promising target for cancer therapy
Methods: The molecular docking process was performed using Molecular Operation Environment (MOE) software to predict mode of interaction between the best possible biological conformations of compounds in the active site of CA IX enzyme. The 2D structures of compounds were prepared by Chem Draw ultra 8.0 software and converted into 3D format by Hyper Chem7 using AM1 semi-empirical method. The compounds were docked into active site of CA IX (PDB ID: 5FL4) by MOE software. The best pose of compounds with the higher score was selected for ligand-target interaction analysis by LigX module in MOE software.
Results: The docking results showed a high docking score (-14.37 kcal/mol) for the most active compound of benzenesulfonamides in comparison to that of the least active compound (-12.97 kcal/mol) and also, CA IX enzyme is a zinc-dependent enzyme and zinc atom was coordinated with His 94, His 96 and His 119 as well as the NH2 group of the compounds.
Conclusion: The docking studies showed interaction mode of benzenesulfonamide derivatives with CAIX including zinc ion coordination, strong hydrophobic interactions and formation of hydrogen bond with benzenesulfonamide. The amine group of sulfonamide part as scaffold and the bulk groups as a hydrophobic part were key factors to improve inhibitory activity of CA IX and design more potent CA IX inhibitors for the therapeutic of cancer.
Keywords: cancer, carbonic anhydrase IX, molecular docking, benzenesulfonamides