复合肽大环优化:结合核磁共振约束和构象分析指导基于结构和配体的设计

IF 3 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Ajay N. Jain, Alexander C. Brueckner, Christine Jorge, Ann E. Cleves, Purnima Khandelwal, Janet Caceres Cortes, Luciano Mueller
{"title":"复合肽大环优化:结合核磁共振约束和构象分析指导基于结构和配体的设计","authors":"Ajay N. Jain,&nbsp;Alexander C. Brueckner,&nbsp;Christine Jorge,&nbsp;Ann E. Cleves,&nbsp;Purnima Khandelwal,&nbsp;Janet Caceres Cortes,&nbsp;Luciano Mueller","doi":"10.1007/s10822-023-00524-2","DOIUrl":null,"url":null,"abstract":"<div><p>Systematic optimization of large macrocyclic peptide ligands is a serious challenge. Here, we describe an approach for lead-optimization using the PD-1/PD-L1 system as a retrospective example of moving from initial lead compound to clinical candidate. We show how conformational restraints can be derived by exploiting NMR data to identify low-energy solution ensembles of a lead compound. Such restraints can be used to focus conformational search for analogs in order to accurately predict bound ligand poses through molecular docking and thereby estimate ligand strain and protein-ligand intermolecular binding energy. We also describe an analogous ligand-based approach that employs molecular similarity optimization to predict bound poses. Both approaches are shown to be effective for prioritizing lead-compound analogs. Surprisingly, relatively small ligand modifications, which may have minimal effects on predicted bound pose or intermolecular interactions, often lead to large changes in estimated strain that have dominating effects on overall binding energy estimates. Effective macrocyclic conformational search is crucial, whether in the context of NMR-based restraints, X-ray ligand refinement, partial torsional restraint for docking/ligand-similarity calculations or agnostic search for nominal global minima. Lead optimization for peptidic macrocycles can be made more productive using a multi-disciplinary approach that combines biophysical data with practical and efficient computational methods.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"37 11","pages":"519 - 535"},"PeriodicalIF":3.0000,"publicationDate":"2023-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10822-023-00524-2.pdf","citationCount":"0","resultStr":"{\"title\":\"Complex peptide macrocycle optimization: combining NMR restraints with conformational analysis to guide structure-based and ligand-based design\",\"authors\":\"Ajay N. Jain,&nbsp;Alexander C. Brueckner,&nbsp;Christine Jorge,&nbsp;Ann E. Cleves,&nbsp;Purnima Khandelwal,&nbsp;Janet Caceres Cortes,&nbsp;Luciano Mueller\",\"doi\":\"10.1007/s10822-023-00524-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Systematic optimization of large macrocyclic peptide ligands is a serious challenge. Here, we describe an approach for lead-optimization using the PD-1/PD-L1 system as a retrospective example of moving from initial lead compound to clinical candidate. We show how conformational restraints can be derived by exploiting NMR data to identify low-energy solution ensembles of a lead compound. Such restraints can be used to focus conformational search for analogs in order to accurately predict bound ligand poses through molecular docking and thereby estimate ligand strain and protein-ligand intermolecular binding energy. We also describe an analogous ligand-based approach that employs molecular similarity optimization to predict bound poses. Both approaches are shown to be effective for prioritizing lead-compound analogs. Surprisingly, relatively small ligand modifications, which may have minimal effects on predicted bound pose or intermolecular interactions, often lead to large changes in estimated strain that have dominating effects on overall binding energy estimates. Effective macrocyclic conformational search is crucial, whether in the context of NMR-based restraints, X-ray ligand refinement, partial torsional restraint for docking/ligand-similarity calculations or agnostic search for nominal global minima. Lead optimization for peptidic macrocycles can be made more productive using a multi-disciplinary approach that combines biophysical data with practical and efficient computational methods.</p></div>\",\"PeriodicalId\":621,\"journal\":{\"name\":\"Journal of Computer-Aided Molecular Design\",\"volume\":\"37 11\",\"pages\":\"519 - 535\"},\"PeriodicalIF\":3.0000,\"publicationDate\":\"2023-08-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://link.springer.com/content/pdf/10.1007/s10822-023-00524-2.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Computer-Aided Molecular Design\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://link.springer.com/article/10.1007/s10822-023-00524-2\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Computer-Aided Molecular Design","FirstCategoryId":"99","ListUrlMain":"https://link.springer.com/article/10.1007/s10822-023-00524-2","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

大环肽配体的系统优化是一个严峻的挑战。在这里,我们描述了一种利用PD-1/PD-L1系统进行导联优化的方法,作为从最初的先导化合物到临床候选化合物的回顾性例子。我们展示了如何通过利用核磁共振数据来识别先导化合物的低能溶液系综来推导构象约束。这些约束可以用于对类似物的集中构象搜索,通过分子对接准确预测结合配体位姿,从而估计配体应变和蛋白质-配体分子间结合能。我们还描述了一种类似的基于配体的方法,该方法采用分子相似性优化来预测束缚姿势。这两种方法都被证明是有效的优先考虑铅化合物类似物。令人惊讶的是,相对较小的配体修饰对预测的结合位姿或分子间相互作用的影响可能微乎其微,但往往会导致估计应变的巨大变化,而这些变化对总体结合能的估计具有主导作用。有效的大环构象搜索是至关重要的,无论是在基于核磁共振的约束、x射线配体优化、对接/配体相似性计算的部分扭转约束或名义全局最小值的不确定搜索的背景下。利用多学科的方法,结合生物物理数据和实用高效的计算方法,可以使肽大环的先导物优化更有成效。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Complex peptide macrocycle optimization: combining NMR restraints with conformational analysis to guide structure-based and ligand-based design

Complex peptide macrocycle optimization: combining NMR restraints with conformational analysis to guide structure-based and ligand-based design

Systematic optimization of large macrocyclic peptide ligands is a serious challenge. Here, we describe an approach for lead-optimization using the PD-1/PD-L1 system as a retrospective example of moving from initial lead compound to clinical candidate. We show how conformational restraints can be derived by exploiting NMR data to identify low-energy solution ensembles of a lead compound. Such restraints can be used to focus conformational search for analogs in order to accurately predict bound ligand poses through molecular docking and thereby estimate ligand strain and protein-ligand intermolecular binding energy. We also describe an analogous ligand-based approach that employs molecular similarity optimization to predict bound poses. Both approaches are shown to be effective for prioritizing lead-compound analogs. Surprisingly, relatively small ligand modifications, which may have minimal effects on predicted bound pose or intermolecular interactions, often lead to large changes in estimated strain that have dominating effects on overall binding energy estimates. Effective macrocyclic conformational search is crucial, whether in the context of NMR-based restraints, X-ray ligand refinement, partial torsional restraint for docking/ligand-similarity calculations or agnostic search for nominal global minima. Lead optimization for peptidic macrocycles can be made more productive using a multi-disciplinary approach that combines biophysical data with practical and efficient computational methods.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Journal of Computer-Aided Molecular Design
Journal of Computer-Aided Molecular Design 生物-计算机:跨学科应用
CiteScore
8.00
自引率
8.60%
发文量
56
审稿时长
3 months
期刊介绍: The Journal of Computer-Aided Molecular Design provides a form for disseminating information on both the theory and the application of computer-based methods in the analysis and design of molecules. The scope of the journal encompasses papers which report new and original research and applications in the following areas: - theoretical chemistry; - computational chemistry; - computer and molecular graphics; - molecular modeling; - protein engineering; - drug design; - expert systems; - general structure-property relationships; - molecular dynamics; - chemical database development and usage.
×
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