title: Molecular mechanism of R-bicalutamide switching from androgen receptor antagonist to agonist induced by amino acid mutations using molecular dynamics simulations and free energy calculation.
abstract: R-bicalutamide, a first generation antiandrogen, was used to treat prostate cancer for decades. Although it is very effective at the beginning, resistance appears after 2-3 years of treatment. Mutation of androgen receptor (AR) is considered a main reason for drug resistance. It is reported that AR W741C, W741L, W741C_T877A, T877A, F876L, F876L_T877A and L701H mutations can convert R-bicalutamide from AR antagonist to agonist, but the switching mechanisms are not clear. In this study, molecular dynamics simulations and molecular mechanics generalized Born surface area (MM-GBSA) calculations were performed to analyze the interaction mechanisms between R-bicalutamide and wild type/mutant ARs. The results indicate that helix H12, which lies on the top of AR LBD like a cover, plays a vital role in R-bicalutamide binding. When interacting with AR, the B-ring of R-bicalutamide pushes H12 aside, distorting the coactivator binding site (AF2) resulting in the inactivation of transcription. Several residue mutations appear to enlarge the distance between the B-ring of R-bicalutamide and H12, reducing steric clash, which is conducive to a closed H12 conformation, leading to the formation of the coactivator binding site AF2 and increased transcription. Hydrogen bond and per-residue free energy decomposition analyses are also investigated to explore the interacting mechanisms, and M895 is found to be a key residue in the antagonist mechanism. The obtained molecular mechanisms will aid rational screening and design of novel AR antagonists, even to mutant AR.
authors.affiliation: School of Pharmacy, Lanzhou University, 199 West Donggang Rd., Lanzhou, 730000, China.
authors.forename: Hongli
authors.initials: H
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Lanzhou University, 199 West Donggang Rd., Lanzhou, 730000, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Han
authors.affiliation: School of Pharmacy, Lanzhou University, 199 West Donggang Rd., Lanzhou, 730000, China. lijiazhong@lzu.edu.cn.
authors.forename: Jiazhong
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Pharmacy, Lanzhou University, 199 West Donggang Rd., Lanzhou, 730000, China.
authors.forename: Huanxiang
authors.initials: H
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Lanzhou University, 199 West Donggang Rd., Lanzhou, 730000, China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Zheng
mesh_terms: D000596:Amino Acids / Q000235:genetics*; D059002:Androgen Receptor Antagonists / Q000737:chemistry*; D000728:Androgens / Q000737:chemistry*; D000813:Anilides / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry*; D001665:Binding Sites; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009570:Nitriles / Q000737:chemistry*; D011944:Receptors, Androgen / Q000737:chemistry* / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014105:Tosyl Compounds / Q000737:chemistry*
chemical_list: D000596:Amino Acids; D059002:Androgen Receptor Antagonists; D000728:Androgens; D000813:Anilides; D000970:Antineoplastic Agents; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C053541:bicalutamide
keywords: Androgen receptor antagonist; Drug-resistant mechanism; MM-GBSA; Molecular dynamics simulations; R-bicalutamide