Discovery of Novel Inhibitors of BRD4 for Treating Prostate Cancer: A Comprehensive Case Study for Considering Water Networks in Virtual Screening and Drug Design

Androgen receptor (AR) is the primary target for treating
prostate
cancer (PCa), which inevitably progresses due to drug-resistant mutations.
Bromodomain-containing protein 4 (BRD4) has been a new potential drug
target for PCa treatment. Herein, we report the rational design and
discovery of novel BRD4 inhibitors through computer-aided drug design
(CADD), and a hit compound SQ-1 (IC50 = 676 nM) was identified
by structure-based virtual screening (SBVS) with the conserved water
network. To optimize the structure of SQ-1, the free energy landscape
was constructed, and the binding mechanism was explored by characterizing
the water profile and the dissociation mechanism. Finally, the compound
SQ-17 with improved inhibitory activity (IC50 < 100
nM) was discovered, which showed potent antiproliferative activity
against LNCaP. These data highlighted a successful attempt to identify
and optimize a small molecule by comprehensive CADD application and
provided essential clues for developing novel therapeutics for PCa
treatment.