Discovery of GlyT2 Inhibitors Using Structure-Based Pharmacophore Screening and Selectivity Studies by FEP plus Calculations
Discovery of GlyT2 Inhibitors Using Structure-Based Pharmacophore Screening and Selectivity Studies by FEP plus Calculations
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DOI：
10.1021/acsmedchemlett.9b00003
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发表时间：
2019-06-01
影响因子：
4.2
通讯作者：
Sirimulla, Suman
中科院分区：
文献类型：
--
作者：
Fratev, Filip;Miranda-Arango, Manuel;Sirimulla, Suman
近年来，哺乳动物甘氨酸转运蛋白2（GlyT2）已成为开发抗慢性疼痛状态的化合物的有希望的靶点。在我们当前的工作中，我们发现了一组新的有希望的命中物，它们在纳摩尔和微摩尔活性下抑制甘氨酸转运蛋白，并且使用新设计的虚拟筛选（VS）方案对GlyT 1具有出色的选择性（如体外研究所示），该方案结合了基于结构的药效团和对接筛选，成功率为75%。此外，自由能微扰计算和分子动力学（MD）的研究揭示了甘氨酸和我们的Hit1化合物的结合和选择性的关键GlyT2氨基酸残基。FEP+结果与可用的文献突变数据非常匹配，证明了生成的GlyT2结构的质量。在这些结果的基础上，我们提出，我们的热门化合物可能会导致新的慢性疼痛药物，以解决未满足和具有挑战性的临床需求。
In recent years, mammalian Glycine transporter 2 (GlyT2) has emerged as a promising target for the development of compounds against chronic pain states. In our current work, we discovered a new set of promising hits that inhibit the glycine transporter at nano- and micromolar activity and have excellent selectivity over GlyT1 (as shown by in vitro studies) using a newly designed virtual screening (VS) protocol that combines a structure-based pharmacophore and docking screens with a success rate of 75%. Furthermore, the free energy perturbation calculations and molecular dynamics (MD) studies revealed the GlyT2 amino acid residues critical for the binding and selectivity of both Glycine and our Hit1 compound. The FEP+ results well-matched with the available literature mutational data proving the quality of the generated GlyT2 structure. On the basis of these results, we propose that our hit compounds may lead to new chronic pain agents to address unmet and challenging clinical needs.