Discovery of Novel Inhibitors of BRD4 for Treating Prostate Cancer: A Comprehensive Case Study for Considering Water Networks in Virtual Screening and Drug Design.
Haiyang ZhongXinyue WangShicheng ChenZhe WangHuating WangLei XuTing-Jun HouXiao-Jun YaoDan LiPeichen PanPublished in: Journal of medicinal chemistry (2023)
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 (IC 50 = 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 (IC 50 < 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.
Keyphrases
- small molecule
- prostate cancer
- drug resistant
- protein protein
- multidrug resistant
- radical prostatectomy
- acinetobacter baumannii
- photodynamic therapy
- adverse drug
- transcription factor
- drug induced
- combination therapy
- pseudomonas aeruginosa
- amino acid
- cystic fibrosis
- climate change
- human health
- dna binding
- light emitting
- network analysis