Accounting for ligand‐bound metal ions in docking small molecules on adenylyl cyclase toxins

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The adenylyl cyclase toxins produced by bacteria (such as the edema factor (EF) of Bacillus anthracis and CyaA of Bordetella pertussis) are important virulence factors in anthrax and whooping cough. Co-crystal structures of these proteins differ in the number and positioning of metal ions in the active site. Metal ions bound only to the ligands in the crystal structures are not included during the docking. To determine what effect these "missing" metals have on docking results, the AutoDock, LigandFit/Cerius2, and FlexX programs were compared for their ability to correctly place substrate analogues and inhibitors into the active sites of the crystal structures of EF, CyaA, and mammalian adenylate cyclase. Protonating the phosphates of substrate analogues improved the accuracy of docking into the active site of CyaA, where the grid did not account for one of the three Mg2+ ions in the crystal structure. The AutoDock ranking (based on docking energies) of a test group of compounds was relatively unaffected by protonation of carboxyl groups. However, the ranking by FlexX-ChemScore varied significantly, especially for docking to CyaA, suggesting that alternate protonation states should be tested when screening compound libraries with this program. When the charges on the bound metal were set correctly, AutoDock was the most reliable program of the three tested with respect to positioning substrate analogues and ranking compounds according to their experimentally determined ability to inhibit EF.