Conformational analysis and docking study of potent factor XIIIa inhibitors having a cyclopropenone ring

A conformational analysis and docking study of potent factor XIIIa inhibitors having a cyclopropenone ring were carried out in an attempt to obtain structural insight into the inhibition mechanism. First, stable conformers of the inhibitors alone were obtained from the conformational analysis by systematic search and molecular dynamics. Next, a binding form model of factor XIIIa was built based on an X-ray crystal structure of the enzyme. Finally, the docking study of the inhibitors into the model’s binding site was performed. From the resulting stable complex structures, it was found that the cyclopropenone ring fits the active site located at the base of the binding cavity with high complementarity. The carbonyl oxygen of the cyclopropenone ring formed a hydrogen bond to the indole NH group of Trp279 and the terminal carbon atom of the reactive CC double bond was in close proximity to the sulfur atom of the catalytic residue, Cys314. This binding mode suggests a possible inhibition mechanism, whereby the cysteine residue reacts with the cyclopropenone ring of the inhibitor, forming an enzyme-ligand adduct. In addition, the higher interaction energies between factor XIIIa and the inhibitors alluded to the probable binding sites of the ligand side chain.