具有gaba -能和谷氨酸能活性的2-(2-氧吡咯烷-1-基)-乙酰胺n -酰基衍生物的分子设计

I. Kodonidi, A. Chiriapkin, D. Tworowski
{"title":"具有gaba -能和谷氨酸能活性的2-(2-氧吡咯烷-1-基)-乙酰胺n -酰基衍生物的分子设计","authors":"I. Kodonidi, A. Chiriapkin, D. Tworowski","doi":"10.19163/2307-9266-2021-9-1-84-97","DOIUrl":null,"url":null,"abstract":"The first of the most successfully implemented nootropic drugs in medical practice is piracetam, which should be attributed to cyclic derivatives of gamma-aminobutyric acid. The production of new piracetam derivatives with high nootropic activity is a promising direction in the development of new neuroprotective drugs.The aim of the study is to predict GABA-ergic and glutamatergic activities of N-acyl derivatives of 2-(2-oxopyrolidin-1-yl)- acetamide by a molecular docking method through the energy analysis of interaction of modeled structures with GABAA and AMPA receptors with their subsequent targeted synthesis.Materials and methods. The objects of the research are new N-acyl derivatives of 2-oxo-1-pyrrolidineacetamide and a virtual model of the GABAA receptor of the Homo sapiens organism with the identification code 6D6U and a three-dimensional model of the AMPA-receptor of the Rattus norvegicus organism with the identification code 3LSF from the RCSB PDB database. The simulated compounds were designed in the HyperChem 8.0.8 program. This program was also used to optimize geometry using the force field of molecular mechanics MM+. Molecular docking was carried out using the Molegro Virtual Docker 6.0.1 program. The preparation of N-acyl derivatives of 2-(2-oxopyrrolidin-1-yl)-acetamide was carried out by the interaction of 2-(2-oxopyrrolidin-1-yl)-acetamide with an excess of the corresponding anhydride under conditions of acid catalysis.Results. Based on the results of molecular docking, a high affinity of all simulated compounds for the binding site of GABAA and AMPA receptors can be estimated. According to the predict, the maximum GABA-ergic activity should be expected for (N-[2-(2-oxopyrrolidin-1-yl)-acetyl]-butyramide. N-acyl derivatives of 2-oxo-1-pyrrolidineacetamide form a more stable complex with amino acid residues Arg207, Phe200, Thr202, Tyr97, Tyr157, Tyr205 and Phe65 of the GABAA receptor binding site than the GABA molecule. In terms of the minimum interaction energy, the N-acyl derivatives of 2-(2-oxopyrrolidin-1-yl)- acetamide are superior to a number of known ligands such as GABA, piracetam, anipiracetam, picamilon and pramiracetam. The tested compounds have also shown a high affinity for the binding site of the AMPA receptor. The leader compound is also the compound PirBut, as in the case of the GABAА receptor.Conclusion. Molecular modeling of the ligands interaction with the active binding site of gamma-aminobutyric acid of the GABAA receptor by molecular docking showed that all virtual N-acyl derivatives of 2-oxo-1-pyrrolidineacetamide can exceed a number of nootropic drugs by activity. In the course of molecular design, a method for predicting a glutamatergic activity for 2-pyrrolidone derivatives has been developed. It suggests a significant nootropic activity for N-[2-(2-oxopyrrolidin-1-yl)- acetamide amides.","PeriodicalId":20025,"journal":{"name":"Pharmacy & Pharmacology","volume":"14 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2021-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"1","resultStr":"{\"title\":\"MOLECULAR DESIGN OF N-ACYL DERIVATIVES OF 2-(2-OXOPYROLIDIN-1-YL)-ACETAMIDE WITH GABA-ERGIC AND GLUTAMATERGIC ACTIVITIES\",\"authors\":\"I. Kodonidi, A. Chiriapkin, D. Tworowski\",\"doi\":\"10.19163/2307-9266-2021-9-1-84-97\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"The first of the most successfully implemented nootropic drugs in medical practice is piracetam, which should be attributed to cyclic derivatives of gamma-aminobutyric acid. The production of new piracetam derivatives with high nootropic activity is a promising direction in the development of new neuroprotective drugs.The aim of the study is to predict GABA-ergic and glutamatergic activities of N-acyl derivatives of 2-(2-oxopyrolidin-1-yl)- acetamide by a molecular docking method through the energy analysis of interaction of modeled structures with GABAA and AMPA receptors with their subsequent targeted synthesis.Materials and methods. The objects of the research are new N-acyl derivatives of 2-oxo-1-pyrrolidineacetamide and a virtual model of the GABAA receptor of the Homo sapiens organism with the identification code 6D6U and a three-dimensional model of the AMPA-receptor of the Rattus norvegicus organism with the identification code 3LSF from the RCSB PDB database. The simulated compounds were designed in the HyperChem 8.0.8 program. This program was also used to optimize geometry using the force field of molecular mechanics MM+. Molecular docking was carried out using the Molegro Virtual Docker 6.0.1 program. The preparation of N-acyl derivatives of 2-(2-oxopyrrolidin-1-yl)-acetamide was carried out by the interaction of 2-(2-oxopyrrolidin-1-yl)-acetamide with an excess of the corresponding anhydride under conditions of acid catalysis.Results. Based on the results of molecular docking, a high affinity of all simulated compounds for the binding site of GABAA and AMPA receptors can be estimated. According to the predict, the maximum GABA-ergic activity should be expected for (N-[2-(2-oxopyrrolidin-1-yl)-acetyl]-butyramide. N-acyl derivatives of 2-oxo-1-pyrrolidineacetamide form a more stable complex with amino acid residues Arg207, Phe200, Thr202, Tyr97, Tyr157, Tyr205 and Phe65 of the GABAA receptor binding site than the GABA molecule. In terms of the minimum interaction energy, the N-acyl derivatives of 2-(2-oxopyrrolidin-1-yl)- acetamide are superior to a number of known ligands such as GABA, piracetam, anipiracetam, picamilon and pramiracetam. The tested compounds have also shown a high affinity for the binding site of the AMPA receptor. The leader compound is also the compound PirBut, as in the case of the GABAА receptor.Conclusion. Molecular modeling of the ligands interaction with the active binding site of gamma-aminobutyric acid of the GABAA receptor by molecular docking showed that all virtual N-acyl derivatives of 2-oxo-1-pyrrolidineacetamide can exceed a number of nootropic drugs by activity. In the course of molecular design, a method for predicting a glutamatergic activity for 2-pyrrolidone derivatives has been developed. It suggests a significant nootropic activity for N-[2-(2-oxopyrrolidin-1-yl)- acetamide amides.\",\"PeriodicalId\":20025,\"journal\":{\"name\":\"Pharmacy & Pharmacology\",\"volume\":\"14 1\",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2021-06-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Pharmacy & Pharmacology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.19163/2307-9266-2021-9-1-84-97\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pharmacy & Pharmacology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.19163/2307-9266-2021-9-1-84-97","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 1

摘要

在医疗实践中,第一种最成功的促智药物是吡拉西坦,它应归因于-氨基丁酸的环衍生物。生产具有高促智活性的吡拉西坦衍生物是开发新型神经保护药物的一个有前途的方向。本研究的目的是通过模型结构与GABAA和AMPA受体相互作用的能量分析以及随后的靶向合成,通过分子对接方法预测2-(2-氧吡咯烷-1-酰基)-乙酰胺n-酰基衍生物的gaba能和谷氨酸能活性。材料和方法。研究对象为新的2-氧-1-吡咯烷乙酰胺n -酰基衍生物和来自RCSB PDB数据库的人类GABAA受体虚拟模型(识别码为6D6U)和褐家鼠ampa受体三维模型(识别码为3LSF)。在HyperChem 8.0.8程序中设计模拟化合物。该程序还用于优化几何利用分子力学的力场MM+。分子对接使用Molegro Virtual Docker 6.0.1程序进行。在酸催化条件下,通过2-(2-氧吡咯烷-1-基)-乙酰胺与过量的相应酸酐相互作用,制备了2-(2-氧吡咯烷-1-基)-乙酰胺的n-酰基衍生物。根据分子对接的结果,可以估计所有模拟化合物对GABAA和AMPA受体结合位点的亲和力都很高。根据预测,(N-[2-(2-氧吡咯烷-1-基)-乙酰基]-丁酰胺的gaba能活性最高。与GABA分子相比,2-氧-1-吡啶乙酰胺的n -酰基衍生物与GABAA受体结合位点的氨基酸残基Arg207、Phe200、Thr202、Tyr97、Tyr157、Tyr205和Phe65形成了更稳定的配合物。在最小相互作用能方面,2-(2- oxopyrolidin -1-yl)-乙酰胺的n-酰基衍生物优于GABA、吡拉西坦、阿尼吡拉西坦、picamilon和priracetam等许多已知配体。测试的化合物也显示出对AMPA受体结合位点的高亲和力。先导化合物也是化合物PirBut,就像GABAА受体一样。通过分子对接对配体与GABAA受体γ -氨基丁酸活性结合位点相互作用的分子模拟表明,2-氧-1-吡咯烷乙酰胺的所有虚拟n -酰基衍生物的活性都可以超过许多益智药物。在分子设计过程中,提出了一种预测2-吡咯烷酮衍生物谷氨酸能活性的方法。提示N-[2-(2-氧吡咯烷-1-酰基)-乙酰胺酰胺具有显著的促智活性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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
MOLECULAR DESIGN OF N-ACYL DERIVATIVES OF 2-(2-OXOPYROLIDIN-1-YL)-ACETAMIDE WITH GABA-ERGIC AND GLUTAMATERGIC ACTIVITIES
The first of the most successfully implemented nootropic drugs in medical practice is piracetam, which should be attributed to cyclic derivatives of gamma-aminobutyric acid. The production of new piracetam derivatives with high nootropic activity is a promising direction in the development of new neuroprotective drugs.The aim of the study is to predict GABA-ergic and glutamatergic activities of N-acyl derivatives of 2-(2-oxopyrolidin-1-yl)- acetamide by a molecular docking method through the energy analysis of interaction of modeled structures with GABAA and AMPA receptors with their subsequent targeted synthesis.Materials and methods. The objects of the research are new N-acyl derivatives of 2-oxo-1-pyrrolidineacetamide and a virtual model of the GABAA receptor of the Homo sapiens organism with the identification code 6D6U and a three-dimensional model of the AMPA-receptor of the Rattus norvegicus organism with the identification code 3LSF from the RCSB PDB database. The simulated compounds were designed in the HyperChem 8.0.8 program. This program was also used to optimize geometry using the force field of molecular mechanics MM+. Molecular docking was carried out using the Molegro Virtual Docker 6.0.1 program. The preparation of N-acyl derivatives of 2-(2-oxopyrrolidin-1-yl)-acetamide was carried out by the interaction of 2-(2-oxopyrrolidin-1-yl)-acetamide with an excess of the corresponding anhydride under conditions of acid catalysis.Results. Based on the results of molecular docking, a high affinity of all simulated compounds for the binding site of GABAA and AMPA receptors can be estimated. According to the predict, the maximum GABA-ergic activity should be expected for (N-[2-(2-oxopyrrolidin-1-yl)-acetyl]-butyramide. N-acyl derivatives of 2-oxo-1-pyrrolidineacetamide form a more stable complex with amino acid residues Arg207, Phe200, Thr202, Tyr97, Tyr157, Tyr205 and Phe65 of the GABAA receptor binding site than the GABA molecule. In terms of the minimum interaction energy, the N-acyl derivatives of 2-(2-oxopyrrolidin-1-yl)- acetamide are superior to a number of known ligands such as GABA, piracetam, anipiracetam, picamilon and pramiracetam. The tested compounds have also shown a high affinity for the binding site of the AMPA receptor. The leader compound is also the compound PirBut, as in the case of the GABAА receptor.Conclusion. Molecular modeling of the ligands interaction with the active binding site of gamma-aminobutyric acid of the GABAA receptor by molecular docking showed that all virtual N-acyl derivatives of 2-oxo-1-pyrrolidineacetamide can exceed a number of nootropic drugs by activity. In the course of molecular design, a method for predicting a glutamatergic activity for 2-pyrrolidone derivatives has been developed. It suggests a significant nootropic activity for N-[2-(2-oxopyrrolidin-1-yl)- acetamide amides.
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
自引率
0.00%
发文量
0
期刊最新文献
USE OF SEQUENCING METHODS FOR SPECIES IDENTIFICATION EXEMPLIFIED BY PHYLOGENETIC RELATIONSHIPS WITHIN GENUS HEDYSARUM L. CLINICAL AND ECONOMIC JUSTIFICATION OF SOFTWARE SCREENING PERFORMANCE OF COLORECTAL CANCER AT THE REGION LEVEL STUDY OF CLINICAL AND PATHOGENETIC EFFECTS OF ANTI-VIRAL DRUG BASED ON FAVIPIRAVIR IN COMORBID PATIENTS WITH COVID-19 AT THE OUTPATIENT STAGE OF TREATMENT ANALYSIS OF THE PERSONNEL’S CONSISTENT READINESS FOR CHANGES AS ILLUSTRATED BY THE EXAMPLE OF AN EXPORT-ORIENTED BIOTECHNOLOGICAL ENTERPRISE DEVELOPMENT OF PERORAL HYPOLIPIDEMIC FORMULATION BASED ON SULFATED ARABINOGALACTAN IN THE FORM OF POTASSIUM SALT
×
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