Characterisation of the flexibility of substrate binding loop in the binding of direct InhA inhibitors.

Q4 Pharmacology, Toxicology and Pharmaceutics International Journal of Computational Biology and Drug Design Pub Date : 2013-01-01 Epub Date: 2013-09-30 DOI:10.1504/IJCBDD.2013.056795
Vivek Kumar, M Elizabeth Sobhia
{"title":"Characterisation of the flexibility of substrate binding loop in the binding of direct InhA inhibitors.","authors":"Vivek Kumar,&nbsp;M Elizabeth Sobhia","doi":"10.1504/IJCBDD.2013.056795","DOIUrl":null,"url":null,"abstract":"<p><p>The substrate binding loop (SBL) of inhA shows conformational changes on binding of direct inhA inhibitors (DIIs). The knowledge of conformational changes and its importance in binding of DII to inhA has not been explored before. This study initially focused on studying the conformational changes of SBL in selected inhA crystal structures. These conformational changes are measured as angle of rotation for SBL from the static hinge region, Ile194, in the crystal structures. The maximal angle difference of ∼41° was observed between most open and closed conformation of SBL. To gain insights into these conformational changes, comparative molecular dynamics simulations of inhA bound with a direct inhibitor (Genz10850) and apoprotein were performed. A considerable variation in the angle of rotation (∼24° to ∼12°) for the SBL which led to the closed conformation was observed during binding of Genz10850 with a consistent increase in electrostatic energy, whereas no change was observed in apoprotein. Hence, conformational changes in the SBL under the influence of inhibitor can be utilised as a parameter for enhanced binding inhibitor with inhA to screen the potent DIIs. </p>","PeriodicalId":39227,"journal":{"name":"International Journal of Computational Biology and Drug Design","volume":"6 4","pages":"318-42"},"PeriodicalIF":0.0000,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1504/IJCBDD.2013.056795","citationCount":"8","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Computational Biology and Drug Design","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1504/IJCBDD.2013.056795","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2013/9/30 0:00:00","PubModel":"Epub","JCR":"Q4","JCRName":"Pharmacology, Toxicology and Pharmaceutics","Score":null,"Total":0}
引用次数: 8

Abstract

The substrate binding loop (SBL) of inhA shows conformational changes on binding of direct inhA inhibitors (DIIs). The knowledge of conformational changes and its importance in binding of DII to inhA has not been explored before. This study initially focused on studying the conformational changes of SBL in selected inhA crystal structures. These conformational changes are measured as angle of rotation for SBL from the static hinge region, Ile194, in the crystal structures. The maximal angle difference of ∼41° was observed between most open and closed conformation of SBL. To gain insights into these conformational changes, comparative molecular dynamics simulations of inhA bound with a direct inhibitor (Genz10850) and apoprotein were performed. A considerable variation in the angle of rotation (∼24° to ∼12°) for the SBL which led to the closed conformation was observed during binding of Genz10850 with a consistent increase in electrostatic energy, whereas no change was observed in apoprotein. Hence, conformational changes in the SBL under the influence of inhibitor can be utilised as a parameter for enhanced binding inhibitor with inhA to screen the potent DIIs.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
直接InhA抑制剂结合的底物结合环的柔韧性表征。
inhA的底物结合环(SBL)在与直接inhA抑制剂(DIIs)结合时表现出构象变化。关于DII与inhA结合的构象变化及其重要性的知识以前没有被探索过。本研究最初的重点是研究SBL在选定的inhA晶体结构中的构象变化。这些构象变化是用SBL从晶体结构中的静态铰链区Ile194的旋转角度来测量的。在SBL的大多数开放构象和封闭构象之间观察到最大角度差约41°。为了深入了解这些构象变化,进行了与直接抑制剂(Genz10850)和载脂蛋白结合的inhA的比较分子动力学模拟。在Genz10850结合过程中,观察到SBL的旋转角度(~ 24°至~ 12°)发生了相当大的变化,导致封闭的构象,静电能量持续增加,而载脂蛋白没有观察到变化。因此,在抑制剂的影响下,SBL的构象变化可以作为增强抑制剂与inhA结合的参数,以筛选有效的dii。
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 去求助
来源期刊
International Journal of Computational Biology and Drug Design
International Journal of Computational Biology and Drug Design Pharmacology, Toxicology and Pharmaceutics-Drug Discovery
CiteScore
1.00
自引率
0.00%
发文量
8
期刊最新文献
Assessment and Validation of Emulgel Based Salicylic acid Formulation Development to Drug release and Optimization by Statistical Design EyeRIS: Image-Based Identification of Goats using Iris Advanced DEEPCNN Breast Cancer Mammogram Image Detection and Classification with Butterfly Optimization Algorithm A Unique Noise Detector Developed for the Filtering of X-Ray Images of Bone Fractures Residue Interaction Network analysis and Molecular dynamics simulation of 6K Viroporin: Chikungunya Virus Channel Proteins
×
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
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 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 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1