当前位置: X-MOL 学术BBA Gen. Subj. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Structure-based, multi-targeted drug discovery approach to eicosanoid inhibition: Dual inhibitors of mPGES-1 and 5-lipoxygenase activating protein (FLAP)
Biochimica et Biophysica Acta (BBA) - General Subjects ( IF 3 ) Pub Date : 2020-11-25 , DOI: 10.1016/j.bbagen.2020.129800
Joseph D. Ho , Matthew R. Lee , Charles T. Rauch , Kristen Aznavour , Jonathan S. Park , John G. Luz , Stephen Antonysamy , Bradley Condon , Milan Maletic , Aiping Zhang , Michael J. Hickey , Norman E. Hughes , Srinivasan Chandrasekhar , Ashley V. Sloan , Karen Gooding , Anita Harvey , Xiao-Peng Yu , Steven D. Kahl , Bryan H. Norman

Background

Due to the importance of both prostaglandins (PGs) and leukotrienes (LTs) as pro-inflammatory mediators, and the potential for eicosanoid shunting in the presence of pathway target inhibitors, we have investigated an approach to inhibiting the formation of both PGs and LTs as part of a multi-targeted drug discovery effort.

Methods

We generated ligand-protein X-ray crystal structures of known inhibitors of microsomal prostaglandin E2 synthase-1 (mPGES-1) and the 5-Lipoxygenase Activating Protein (FLAP), with their respective proteins, to understand the overlapping pharmacophores. We subsequently used molecular modeling and structure-based drug design (SBDD) to identify hybrid structures intended to inhibit both targets.

Results

This work enabled the preparation of compounds 4 and 5, which showed potent in vitro inhibition of both targets.

Significance

Our findings enhance the structural understanding of mPGES-1 and FLAP's unique ligand binding pockets and should accelerate the discovery of additional dual inhibitors for these two important integral membrane protein drug targets.



中文翻译:

基于结构的多目标药物发现方法可抑制类花生酸:mPGES-1和5-脂氧合酶激活蛋白(FLAP)的双重抑制剂

背景

由于前列腺素(PGs)和白三烯(LTs)作为促炎性介质的重要性,以及在存在通路靶标抑制剂的情况下类花生酸分流的潜力,我们研究了一种抑制PGs和LTs形成的方法。多目标药物发现工作的一部分。

方法

我们生成了已知的微粒体前列腺素E2合酶1(mPGES-1)和5-脂氧合酶激活蛋白(FLAP)的抑制剂的配体蛋白X射线晶体结构,以及它们各自的蛋白质,以了解重叠的药效团。随后,我们使用了分子建模和基于结构的药物设计(SBDD)来识别旨在抑制两个靶标的杂合结构。

结果

这项工作使化合物45的制备成为可能,该化合物对两个靶标均显示出有效的体外抑制作用。

意义

我们的发现增强了对mPGES-1和FLAP独特的配体结合口袋的结构理解,并应加快发现这两个重要的整体膜蛋白药物靶标的其他双重抑制剂的速度。

更新日期:2020-12-04
down
wechat
bug