Molecular Dynamics Simulation of Cyclooxygenase-2 Complexes with Indomethacin closo-Carborane Analogs.

Molecular dynamics simulation of carborane-containing ligands in complex with target enzymes is a challenging task due to the unique structure and properties of the carborane substituents and relative lack of appropriate experimental data to help assess the quality of carborane force field parameters. Here, we report results from energy minimization calculations for a series of carborane-amino acid complexes using carborane force field parameters published previously in the literature and adapted for use with the AMBER ff99SB and ff14SB potential functions. These molecular mechanics results agree well with quantum mechanical geometry optimization calculations obtained using dispersion-corrected density functional theory methods, suggesting that the carborane force field parameters should be suitable for more detailed calculations. We then performed molecular dynamics simulations for the 1,2-, 1,7-, and 1,12-dicarba- closo-dodecaborane(12) derivatives of indomethacin methyl ester bound with cyclooxygenase-2. The simulation results suggest that only the ortho-carborane derivative forms a stable complex, in agreement with experimental findings, and provide insight into the possible molecular basis for isomer binding selectivity.