Molecular modeling of carborane-containing drug molecules

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Carborane clusters and their derivatives have recently become the focus of intense research in the fields of medicinal chemistry and drug design. The substitution of organic ring systems with carboranes proved to be a successful strategy towards novel and improved drug molecules. However, only a few crystal structures of carborane-containing drug molecules bound to target proteins are known so far. In lack of experimental data, the molecular modeling studies proposed herein will provide insight into the binding mode of carborane-containing drug molecules to their target biomolecules and into dynamic processes such as dihydrogen bond formation and dissociation between carboranes and the surrounding proteins. Classical molecular mechanics (MM) simulations on carborane-protein systems are not readily achievable, since well calibrated and general purpose force field parameters for carboranes are not yet available. Currently only docking simulations or QM/MM calculations can be used to describe the interactions between carborane-containing drug molecules and biomolecules. Docking simulations can reasonably predict the binding modes of these ligands, but fail to provide accurate binding free energy values. Obtaining free energy values with a low error margin is essential for investigating problems such as the selectivity of cyclooxygenase (COX) inhibitors. Furthermore, the ranking of carborane-containing drug candidates obtained from docking results cannot be refined with the aid of MM free energy calculations due to the lack of adequate carborane force field parameters. The computationally demanding nature of the QM/MM method limits the time scale of molecular dynamic (MD) simulations and restricts the type of achievable calculations. Thus, the main objective of this project is to develop and validate MM force field parameters for carborane-containing drug molecules, such as indomethacin derivatives. The newly developed MM force fields would grant access to much longer time scale MD simulations, at considerably less computational costs, and would grant access to free energy calculations using MM based methods. Furthermore, the newly developed MM force field parameters will provide a starting point for parameterization of similar carborane-containing molecules. A well calibrated carborane force field will considerably aid the discovery and study of potential biologically active carborane-containing compounds.