Homology modeling using multiple molecular dynamics simulations and docking studies of the human androgen receptor ligand binding domain bound to testosterone and nonsteroidal ligands

To facilitate the rational design of novel and more potent androgen recepto r ligands, three-dimensional models for the human androgen receptor ligand binding domain bound to testosterone have been developed. These models of t he androgen receptor were based on the crystal structure of the highly homo logous human progesterone receptor ligand binding domain. The homology mode led androgen receptor was refined using unrestrained multiple molecular dyn amics simulations in explicit solvent, Key H-bonding partners with the 17-h ydroxy group and 3-keto group of testosterone are Asn705 and Thr877, and Gl n711 and Arg752, respectively. These models show the presence of a unique u noccupied cavity within the androgen receptor binding pocket which may be v aluable in the development of novel selective androgen receptor ligands. A qualitative analysis of amino acid mutations within the hAR binding pocket that affect ligand binding are consistent with these androgen receptor mode ls. In addition to testosterone, the binding modes of several hydroxyflutam ide-like nonsteroidal ligands for the androgen receptor are investigated us ing flexible docking with FlexX followed by refinement of the initial compl exes with molecular dynamics simulations. These docking studies indicate th at Asn705 is an important determinant in binding hydroxyflutamide and its d erivatives by participating in II-bond interactions with the a-hydroxy moie ty of these ligands. In addition, the nitro functionality mimics the 3-keto group of the natural ligand testosterone and is involved in II-bonding int eractions with Gln711 and Arg752. From these docking studies, we suggest a mechanism for the enantioselective binding of chiral hydroxyflutamide deriv atives and expand upon the previously reported structure-activity relations hip for hydroxyflutamide and its derivatives.