Optimization of CHARMM force field parameters of a prostate cancer drug enzalutamide

Abstract Enzalutamide is the most recent and potent clinically available drug molecule used to treat castration-resistant metastatic prostate cancer patients. In the presence of certain mutations on the Androgen receptor, enzalutamide fails to function as an antagonist. The molecular mechanism of this resistance has not been understood clearly. Molecular Dynamics (MD) simulations are a powerful tool to investigate such resistance mechanisms. Insights from MD simulations of receptor-ligand complex heavily depend on the quality of the parameters of the ligands. Thus, we developed and optimized CHARMM Force field parameters of enzalutamide. The initial assignment of parameters was done by using the CHARMM General Force Field (CGenFF) program. After that, using the Force Field Tool Kit (FFTK) partial charges, bond, angle and dihedral parameters of enzalutamide were optimized to reproduce quantum mechanics calculation results. For the validation of parameters, water-octanol partition coefficient, Infrared Spectra (IR) and normal mode analysis calculations were performed. In addition, a 300 ns-long MD simulation of enzalutamide was carried out to assess the ability of the optimized parameters in exploring torsional angle space.