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首页> 外文期刊>RSC Advances >Sequential ligand- and structure-based virtual screening approach for the identification of potential G protein-coupled estrogen receptor-1 (GPER-1) modulators
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Sequential ligand- and structure-based virtual screening approach for the identification of potential G protein-coupled estrogen receptor-1 (GPER-1) modulators

机译：基于配体和结构的虚拟筛选方法，用于识别潜在的G蛋白偶联雌激素受体-1（GPER-1）调节剂

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摘要

G protein-coupled estrogen receptor-1 (GPER-1) is a seven transmembrane receptor, responsible for mediating rapid estrogen signaling in many physiological responses in reproductive, nervous, endocrine, immune and cardiovascular systems. Due to unavailability of the crystal structure of GPER-1, we have performed sequential ligand-based virtual screening (LBVS) and structure-based screening (SBVS) to identify potential GPER-1 modulators. LBVS and SBVS approaches were validated retrospectively using the Receiver Operating Curve (ROC) plot and the early Enrichment Factor (EF). LBVS was performed based on a GPER-1 agonist, G1, as a query model for screening of the eMolecules library using the Rapid Overlay of Chemical Structure (ROCS) and the electrostatic potential screening (EON) approaches. Top-scored hits from LBVS were further screened by SBVS. SBVS was based on generating homology models of GPER-1 and subsequent molecular docking studies. Using Chemguass4 score, we filtered the final hits with the higher score in comparison to G1 (Chemguass4 score = -11.575). The top-ranked hits were clustered based on similarity in their scaffolds. Prospective validation was performed by evaluating the antiproliferative activity of synthesized compounds (SK0 and SK0P) which were representative of top hits obtained from our virtual screening approach.
机译：G蛋白偶联雌激素受体-1（GPER-1）是七种跨膜受体，其负责在生殖，神经，内分泌，免疫和心血管系统中的许多生理反应中介导快速雌激素信号。由于GPER-1的晶体结构的不可用，我们已经执行了基于顺序的基于配体的虚拟筛选（LBV）和基于结构的筛选（SBV）以识别电位的GPER-1调制器。使用接收器操作曲线（ROC）图和早期富集因子（EF）回顾性地验证LBV和SBVS方法。基于GPER-1激动剂G1执行LBV，作为使用化学结构（ROC）的快速覆盖和静电潜在筛选（EON）方法的用于筛选铸造库的查询模型。 SBV进一步筛选来自LBV的最高评分命中。 SBV基于产生GPER-1的同源模型和随后的分子对接研究。使用ChemGuass4得分，我们与G1（ChemGuass4得分= -11.575）相比过得分的最终命中。基于脚手架中的相似性集群，排名排名的命中。通过评估代表从我们的虚拟筛选方法获得的顶部命中的合成化合物（SK0和SK0P）的抗增殖活性来进行前瞻性验证。

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  • 来源
    《RSC Advances》 |2019年第5期|共14页
  • 作者

    Khan Shafi Ullah; Ahemad Nafees; Chuah Lay-Hong; Naidu Rakesh; Htar Thet Thet;

  • 作者单位

    Monash Univ Malaysia Sch Pharm Jalan Lagoon Selatan Bandar Sunway Subang Jaya 47500 Selangor Malaysia;

    Monash Univ Malaysia Sch Pharm Jalan Lagoon Selatan Bandar Sunway Subang Jaya 47500 Selangor Malaysia;

    Monash Univ Malaysia Sch Pharm Jalan Lagoon Selatan Bandar Sunway Subang Jaya 47500 Selangor Malaysia;

    Monash Univ Malaysia Jeffrey Cheah Sch Med &

    Hlth Sci Jalan Lagoon Selatan Bandar Sunway Subang Jaya 47500 Selangor Malaysia;

    Monash Univ Malaysia Sch Pharm Jalan Lagoon Selatan Bandar Sunway Subang Jaya 47500 Selangor Malaysia;

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  • 正文语种 eng
  • 中图分类 化学;
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