Design of Novel Compounds with the Potential of Dual PPARγ/α Modulation for the Management of Metabolic Syndrome

C. Ellul, C. Shoemake
{"title":"Design of Novel Compounds with the Potential of Dual PPARγ/α Modulation for the Management of Metabolic Syndrome","authors":"C. Ellul, C. Shoemake","doi":"10.11131/2017/101311","DOIUrl":null,"url":null,"abstract":"This study sought to identify a single molecule capable of managing all three manifestations of metabolic syndrome–hyperglycaemia, dyslipidaemia and hypertension. Two Protein Data Bank (PDB) depositions were selected and used to establish the baseline affinity that any designed molecule in this study should ideally exceed in order to be considered for further optimisation. These were PDB depositions 3VN2 and 2P54 describing the bound co-ordinates of the Peroxisome Proliferator Activated Receptor (PPAR)γ partial agonist and Angiotensin II Receptor (Ang(II)R) blocker telmisartan and of the experimental PPARα fibrate agonist GW590735 bound to their respective cognate receptors. These small molecules were extracted from their cognate receptors, docked into their non-cognate counterparts, conformational analysis performed, and the optimal conformers were selected as template scaffolds in two parallel processes. The first was a fragment based de novo approach. Here, molecular moieties from the optimal telmisartan and GW590735 scaffolds modelled in their non-cognate targets and considered critical to binding were identified and modelled, in order to produce seed structures capable of sustaining molecular growth at user-directed sites designated as H.spc atoms subsequent to their being docked within the non-cognate Ligand Binding Pockets (LBPs). The second approach was a Virtual Screening (VS) exercise. Here, the optimal telmisartan and GW590735 conformers were submitted as query molecules to VS databases both individually and in the form of a consensus pharmacophore. This VS exercise identified structurally diverse molecules which were electronically and spatially similar to the queries and which were capable of modulating the target receptors. The molecular cohorts identified through both VS and the de novo approaches were filtered for Lipinski Rule compliance. The molecules that survived filtering were then re-docked into the non-cognate PPARα and/or γ_LBPs, conformational analysis re-performed and the affinity of the optimal conformer measured for its cognate receptor quantified. Comparison was made to the baseline and non-cognate receptor affinities previously established, and the molecules exhibiting dual affinities exceeding baseline values were selected for further optimisation. The use of the “tried and tested” Ang(II)R blocker and fibrate scaffolds as templates predisposes to the identification of novel structures devoid of unacceptable toxicity.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2017-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nuclear Receptor Research","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.11131/2017/101311","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

Abstract

This study sought to identify a single molecule capable of managing all three manifestations of metabolic syndrome–hyperglycaemia, dyslipidaemia and hypertension. Two Protein Data Bank (PDB) depositions were selected and used to establish the baseline affinity that any designed molecule in this study should ideally exceed in order to be considered for further optimisation. These were PDB depositions 3VN2 and 2P54 describing the bound co-ordinates of the Peroxisome Proliferator Activated Receptor (PPAR)γ partial agonist and Angiotensin II Receptor (Ang(II)R) blocker telmisartan and of the experimental PPARα fibrate agonist GW590735 bound to their respective cognate receptors. These small molecules were extracted from their cognate receptors, docked into their non-cognate counterparts, conformational analysis performed, and the optimal conformers were selected as template scaffolds in two parallel processes. The first was a fragment based de novo approach. Here, molecular moieties from the optimal telmisartan and GW590735 scaffolds modelled in their non-cognate targets and considered critical to binding were identified and modelled, in order to produce seed structures capable of sustaining molecular growth at user-directed sites designated as H.spc atoms subsequent to their being docked within the non-cognate Ligand Binding Pockets (LBPs). The second approach was a Virtual Screening (VS) exercise. Here, the optimal telmisartan and GW590735 conformers were submitted as query molecules to VS databases both individually and in the form of a consensus pharmacophore. This VS exercise identified structurally diverse molecules which were electronically and spatially similar to the queries and which were capable of modulating the target receptors. The molecular cohorts identified through both VS and the de novo approaches were filtered for Lipinski Rule compliance. The molecules that survived filtering were then re-docked into the non-cognate PPARα and/or γ_LBPs, conformational analysis re-performed and the affinity of the optimal conformer measured for its cognate receptor quantified. Comparison was made to the baseline and non-cognate receptor affinities previously established, and the molecules exhibiting dual affinities exceeding baseline values were selected for further optimisation. The use of the “tried and tested” Ang(II)R blocker and fibrate scaffolds as templates predisposes to the identification of novel structures devoid of unacceptable toxicity.
具有双重PPARγ/α调节代谢综合征管理潜力的新化合物的设计
本研究旨在鉴定一种能够治疗代谢综合征(高血糖、血脂异常和高血压)所有三种表现的单分子。选择两种蛋白质数据库(PDB)沉积并用于建立基线亲和力,本研究中任何设计的分子都应该理想地超过该亲和力,以便考虑进一步优化。这些是PDB沉积3VN2和2P54,描述了过氧化物酶体增殖物激活受体(PPAR)γ部分激动剂和血管紧张素II受体(Ang(II)R)阻滞剂替米沙坦和实验PPARα贝特激动剂GW590735与其各自的同源受体结合的结合坐标。这些小分子从它们的同源受体中提取,对接到它们的非同源受体中,进行构象分析,并在两个平行过程中选择最佳构象作为模板支架。第一种是基于片段的从头开始的方法。在这里,来自最佳替米沙坦和GW590735支架的分子片段在其非同源靶标中建模,被认为对结合至关重要,为了产生种子结构,能够在用户导向的位点上维持分子生长,这些位点被指定为H.spc原子,随后它们被停泊在非同源配体结合口袋(lbp)中。第二个方法是虚拟筛选(VS)练习。在这里,最优的替米沙坦和GW590735构象被单独或以共识药效团的形式作为查询分子提交到VS数据库。这个VS练习确定了结构多样的分子,这些分子在电子和空间上与查询相似,并且能够调节目标受体。通过VS和de novo方法确定的分子队列经过利平斯基规则(Lipinski Rule)的过滤。过滤后存活下来的分子被重新连接到非同源的PPARα和/或γ _lbp中,重新进行构象分析,并定量测量其同源受体的最佳构象的亲和力。与先前建立的基线和非同源受体亲和度进行比较,并选择具有超过基线值的双亲和度的分子进行进一步优化。使用“经过试验和测试的”Ang(II)R阻滞剂和贝特支架作为模板,易于鉴定出没有不可接受毒性的新结构。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
自引率
0.00%
发文量
0
审稿时长
12 weeks
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信