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.

Enzalutamide是用于治疗去势抵抗性转移性前列腺癌患者的最新且有效的临床可用药物分子。在雄激素受体上存在某些突变的情况下，enzalutamide不能充当拮抗剂。这种抗性的分子机制还不清楚。分子动力学（MD）模拟是研究此类耐药机制的强大工具。MD模拟受体-配体复合物的见解在很大程度上取决于配体参数的质量。因此，我们开发并优化了enzalutamide的CHARMM力场参数。参数的初始分配是通过使用CHARMM通用力场（CGenFF）程序完成的。之后，使用力场工具包（FFTK）进行部分充电，键合，优化了enzalutamide的角度和二面参数，以重现量子力学计算结果。为了验证参数，执行了辛醇水分配系数，红外光谱（IR）和正常模式分析计算。此外，对enzalutamide进行了300 ns长的MD模拟，以评估优化参数探索扭转角空间的能力。