jm1c01287_si_006.pdb (328.53 kB)
Discovery of a Novel Androgen Receptor Antagonist Manifesting Evidence to Disrupt the Dimerization of the Ligand-Binding Domain via Attenuating the Hydrogen-Bonding Network Between the Two Monomers
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posted on 2021-11-23, 07:08 authored by Weitao Fu, Minkui Zhang, Jianing Liao, Qing Tang, Yixuan Lei, Zhou Gong, Luhu Shan, Mojie Duan, Xin Chai, Jinping Pang, Chun Tang, Xuwen Wang, Xiaohong Xu, Dan Li, Rong Sheng, Tingjun HouAndrogen
receptor (AR) has proved to be a vital drug target for
treating prostate cancer. Here, we reported the discovery of a novel
AR antagonist 92 targeting the AR ligand-binding pocket,
but distinct from the marketed drug enzalutamide (Enz), 92 demonstrated inhibition on the AR ligand-binding domain (LBD) dimerization,
which is a novel mechanism reported for the first time. First, a novel
hit (26, IC50 = 5.57 μM) was identified
through virtual screening based on a theoretical AR LBD dimer bound
with the Enz model. Then, guided by molecular modeling, 92 was discovered with 32.7-fold improved AR antagonistic activity
(IC50 = 0.17 μM). Besides showing high bioactivity
and safety, 92 can inhibit AR nuclear translocation.
Furthermore, 92 inhibited the formation of the AR LBD
dimer, possibly through attenuating the hydrogen-bonding network between
the two monomers. This interesting finding would pave the way for
the discovery of a new class of AR antagonists.
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vital drug targetvirtual screening basedtreating prostate cancermarketed drug enzalutamide17 μm ).novel ar antagonistnovel mechanism reported92 b50 subar lbd dimer57 μmar antagoniststwo monomersnew classmolecular modelingenz modelenz ),demonstrated inhibitionbonding networkbinding pocketbinding domain