A Metalloprotein-specific Scoring Function And Docking Program:Methods And Application

Molecular docking as a promising tool to find and optimize lead compounds has been widely applied in drug discovery in recent years. All docking methods require a conformational search method to explore the possible binding modes, and a scoring function to evaluate and rank the various candidate binding modes. Although several docking algorithms are available, the accuracy improvement for the scoring functions continues to be a major challenge.As promising therapeutic drug targets, metalloproteins have recently attracted great interests in the search of potent and selective inhibitors. So far, there exists a lot of docking programs, while they normally ignore the importance of metal ions, which will indubitably lead to inaccurate performances. Therefore, we developed a novel metalloprotein-specific scoring function aimed at applying to this specific target class. Our method combines the knowledge-based and force field-based scoring function, and adopts restrictive constraints to adjust the coefficients, then introduces an iterative procedure to correct the scoring function during the docking procedure. This specific scoring function can be an appropriate tool to evaluate metalloprotein-ligand interactions, and to accurately predict the predominant binding modes of a ligand with a metalloprotein.Carbonic anhydrases (CAs) are abundant zinc metalloenzymes found in a diversity of organisms, and15different CA isozymes or CA-related proteins (CARP)have been identified in humans. Recently, two tumor-associated membrane carbonic anhydrase isozymes (CA Ⅸ and CA Ⅻ) attracted much more attention. Through virtual screening, some novel sulfonamides hits with high inhibitory activity against CA Ⅸ were previously discovered in our group. In this paper, two lead compounds were identified for further structural optimization. According to the potential binding modes, which were obtained by utilizing the metalloprotein-specific docking program, a series of derivations were synthesized. The following biological assay showed that some compounds exhibited potent inhibitory against CA IX as well as high selectivity against other carbonic anhydrase isozymes(CA I and CA II). Meanwhile, the application for the CA IX inhibitors also validates the practicability of our metalloprotein-specific docking program.