Androgen receptor (AR) is an important target for the treatment of prostate cancer, and mutations in the AR have an important impact on the resistance of existing drugs. In this work, we performed molecular dynamics simulations of the existing marketed antiandrogens flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, darolutamide, and its main metabolite ORM15341 in complex with the wild-type and F876L mutant AR. We calculated the residue-specific binding free energy contribution of the wild-type and mutant ARs with the AS-IE method and analyzed the hotspot residues and the binding free energy contributions of specific residues before and after the mutation. In addition, we analyzed the total binding obtained by adding residue binding energy contributions and compared the results with experimental values. The obtained residue-specific binding information should be very helpful in understanding the mechanism of drug resistance with respect to specific mutations and in the design of new generation drugs against possible new mutations.

中文翻译：

---

第一代和第二代抗雄激素与 F876L 突变的结合模式分析

雄激素受体（AR）是治疗前列腺癌的重要靶点，AR的突变对现有药物的耐药性有重要影响。在这项工作中，我们对现有市售的抗雄激素药物氟他胺、尼鲁他胺、比卡鲁胺、恩杂鲁胺、阿帕鲁胺、达洛鲁胺及其主要代谢物 ORM15341 与野生型和 F876L 突变体 AR 进行了分子动力学模拟。我们用AS-IE方法计算了野生型和突变型ARs的残基特异性结合自由能贡献，并分析了突变前后的热点残基和特定残基的结合自由能贡献。此外，我们分析了通过添加残基结合能贡献获得的总结合，并将结果与​​实验值进行比较。