CHARMM Force Field Parameterization of Rosiglitazone

We develop a CHARMM-based interaction potential for rosiglitazone, a well-known selective ligand to the c isoform of the peroxisome proliferator-activated receptor (PPAR gamma) and widely marketed antidiabetic drug of the thiazolidinedione (TZD) class. We derive partial atomic charges and dihedral torsion potentials for seven rotations in the molecule, for which there are no analogs available in CHARMM. The potential model is validated by performing a series of molecular dynamics simulations of rosiglitazone in neat water and of a fully solvated rosiglitazone-PPAR gamma complex. The structural and dynamical behavior of the complex is analyzed in comparison with available experimental data. The potential parameters derived here are readily transferable to a variety of pharmaceutically important TZD compounds. (C) 2010 Wiley Periodicals, Inc. Int J Quantum Chem 111: 1346-1354, 2011