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Discovery of Novel Inhibitors of BRD4 for Treating Prostate Cancer: A Comprehensive Case Study for Considering Water Networks in Virtual Screening and Drug Design
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-12-28 , DOI: 10.1021/acs.jmedchem.3c00996 Haiyang Zhong 1 , Xinyue Wang 1 , Shicheng Chen 1 , Zhe Wang 1 , Huating Wang 1 , Lei Xu 2 , Tingjun Hou 1 , Xiaojun Yao 3 , Dan Li 1 , Peichen Pan 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-12-28 , DOI: 10.1021/acs.jmedchem.3c00996 Haiyang Zhong 1 , Xinyue Wang 1 , Shicheng Chen 1 , Zhe Wang 1 , Huating Wang 1 , Lei Xu 2 , Tingjun Hou 1 , Xiaojun Yao 3 , Dan Li 1 , Peichen Pan 1
Affiliation
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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.
中文翻译：
发现用于治疗前列腺癌的新型 BRD4 抑制剂：在虚拟筛选和药物设计中考虑水网络的综合案例研究
雄激素受体（AR）是治疗前列腺癌（PCa）的主要靶点，前列腺癌不可避免地会因耐药突变而进展。含溴结构域蛋白 4 (BRD4) 已成为 PCa 治疗的新的潜在药物靶点。在此，我们报告了通过计算机辅助药物设计（CADD）合理设计和发现新型 BRD4 抑制剂，并通过基于结构的虚拟筛选（SBVS）鉴定了热门化合物 SQ-1（IC 50 = 676 nM）节约用水网络。为了优化SQ-1的结构，构建了自由能景观，并通过表征水剖面和解离机制来探索结合机制。最后，发现了具有改善的抑制活性（IC 50 < 100 nM）的化合物SQ-17，其对LNCaP表现出有效的抗增殖活性。这些数据凸显了通过综合 CADD 应用识别和优化小分子的成功尝试，并为开发 PCa 治疗新疗法提供了重要线索。
更新日期：2023-12-28
中文翻译：
发现用于治疗前列腺癌的新型 BRD4 抑制剂：在虚拟筛选和药物设计中考虑水网络的综合案例研究
雄激素受体（AR）是治疗前列腺癌（PCa）的主要靶点，前列腺癌不可避免地会因耐药突变而进展。含溴结构域蛋白 4 (BRD4) 已成为 PCa 治疗的新的潜在药物靶点。在此，我们报告了通过计算机辅助药物设计（CADD）合理设计和发现新型 BRD4 抑制剂，并通过基于结构的虚拟筛选（SBVS）鉴定了热门化合物 SQ-1（IC 50 = 676 nM）节约用水网络。为了优化SQ-1的结构，构建了自由能景观，并通过表征水剖面和解离机制来探索结合机制。最后，发现了具有改善的抑制活性（IC 50 < 100 nM）的化合物SQ-17，其对LNCaP表现出有效的抗增殖活性。这些数据凸显了通过综合 CADD 应用识别和优化小分子的成功尝试，并为开发 PCa 治疗新疗法提供了重要线索。
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