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

Abstract

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.

Atomistic Simulations of COSAN: Amphiphiles without a Head‐and‐Tail Design Display “Head and Tail” Surfactant Behavior

“…[12],t he region delimited by the carbon atoms has al ow charge density, whereas the boron atoms geometrically opposed to this region concentrate the negative charge of the anion. This molecular architecture strongly suggests that cis-COSAN could be as urfactant with the four carbon atoms delimiting the hydrophobic region of the molecule since it is the low charge density region of the molecule.T he boron atoms with high charge density will correspond to the hydrophilic regions of the molecule.T his concept was proved by performing aseries of all-atomic molecular dynamics (MD) simulations [20] of cis-COSAN in water using the NAMD [24] program and aCHARMM36-compatible force field [25][26][27] (see details in the Supporting Information).…”

Boron rich nanotube drug carrier system is suited for boron neutron capture therapy

“…All simulations were performed on a RHCC-NT- o -carborane (C 2 B 10 H 12 ) complex in which all four cavities were simultaneously occupied by a single carborane molecule. The complex was formed by inserting a modeled structure of an o -carborane molecule into each cavity of the measured structure of an RHCC-NT tetramer (PDB code 1FE6) 13 which was crystallized at T = 298 K. The Amber 99 force field parameters for o -carborane were obtained from literature 23 – 25 . Each RHCC-NT complex was solvated in water and Na + ions to neutralize the system.…”

Atomistic Simulations of COSAN: Amphiphiles without a Head‐and‐Tail Design Display “Head and Tail” Surfactant Behavior

“…The boron atoms with high charge density will correspond to the hydrophilic regions of the molecule. This concept was proved by performing a series of all‐atomic molecular dynamics (MD) simulations of cis ‐COSAN in water using the NAMD program and a CHARMM36‐compatible force field (see details in the Supporting Information).…”