Analysis of the binding modes of the first- and second-generation antiandrogens with respect to F876L mutation

Guangfeng Shao, Jingxiao Bao, Xiaolin Pan, Xiao He, Yifei Qi, John Z.H. Zhang

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)60-72
Number of pages13
JournalChemical Biology and Drug Design
Issue number1
StatePublished - Jul 2021


  • androgen receptor
  • antiandrogens
  • binding free energy
  • hot-spot residue

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry


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