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.

雄激素受体（Androgen receptor，AR）是前列腺癌（prostate cancer，PCa）治疗的首要靶点，但该疾病常因耐药突变发生进展。含溴结构域蛋白4（Bromodomain-containing protein 4，BRD4）是近年来新兴的前列腺癌治疗潜在药物靶点。本研究通过计算机辅助药物设计（computer-aided drug design，CADD）方法，理性设计并发现了新型BRD4抑制剂；依托保守水网络的基于结构的虚拟筛选（structure-based virtual screening，SBVS），我们鉴定得到命中化合物SQ-1（半最大抑制浓度IC₅₀ = 676 nM）。为优化SQ-1的分子结构，我们构建了其自由能景观，并通过表征结合过程中的水分布特征与解离机制，深入探究了其结合模式。最终，我们获得了抑制活性显著提升的化合物SQ-17（IC₅₀ < 100 nM），该化合物对LNCaP细胞展现出强效抗增殖活性。本研究通过综合应用计算机辅助药物设计策略，成功实现了小分子化合物的发现与优化，为前列腺癌治疗的新型候选药物研发提供了关键线索。