Abstract

Cancer ranks in second place among the cause of death worldwide. Cancer progress in multiple stages of carcinogenesis and metastasis programs through complex pathways. Sex hormones and their receptors are the major factors in promoting cancer progression. Among them, G protein-coupled estrogen receptor-1 (GPER) has shown to mediate cellular signaling pathways and cancer cell proliferation. However, the lack of GPER protein structure limited the search for new modulators. In this study, we curated an extensive database of natural products to discover new potential GPER modulators. We used a combination of virtual screening techniques to generate a homology model of GPER and subsequently used that for the screening of 30,926 natural products from a public database to identify potential active modulators of GPER. The best hits were further screened through the ADMET filter and confirmed by docking analysis. Moreover, molecular dynamics simulations of best hits were also carried out to assess the stability of the ligand-GPER complex. This study predicted several potential GPER modulators with novel scaffolds that could be further investigated and used as the core for the development of novel GPER modulators.

Communicated by Ramaswamy H. Sarma

摘要

癌症在全球死亡原因中排名第二。癌症在多个阶段的癌变和转移过程中通过复杂的途径进展。性激素及其受体是促进癌症进展的主要因素。其中，G 蛋白偶联雌激素受体-1 (GPER) 已显示介导细胞信号通路和癌细胞增殖。然而，缺乏 GPER 蛋白质结构限制了对新调节剂的寻找。在这项研究中，我们策划了一个广泛的天然产物数据库，以发现新的潜在 GPER 调节剂。我们使用虚拟筛选技术的组合来生成 GPER 的同源模型，随后将其用于从公共数据库中筛选 30,926 种天然产物，以识别 GPER 的潜在活性调节剂。最佳匹配通过 ADMET 过滤器进一步筛选，并通过对接分析确认。此外，还进行了最佳命中的分子动力学模拟，以评估配体-GPER 复合物的稳定性。该研究预测了几种具有新型支架的潜在 GPER 调节剂，可以进一步研究并用作开发新型 GPER 调节剂的核心。

由 Ramaswamy H. Sarma 传达