{"title":"通过基于片段的药物设计(FBDD)和分子动力学模拟策略,发现抑制神经氨酸酶重要功能的新型流感强效药物。","authors":"Lotfi Bourougaa, Mebarka Ouassaf, Amneh Shtaiwi","doi":"10.1080/07391102.2023.2251065","DOIUrl":null,"url":null,"abstract":"<p><p>The current work describes a fragment linking methodology to generate new neuraminidase inhibitors. A total number of 28,977 fragments from Zinc 20 have been obtained and screened for neuraminidase receptor affinity. Using Schrödinger software, the highest-scoring 270 fragment hits (with scores greater than -7.6) were subjected to fragment combining to create 100 new molecules. These 100 novel compounds were studied using XP docking to evaluate the molecular interaction modes and their binding affinity to neuraminidase receptor. The top ten molecules were selected, for ADMET, drug-likeness features. Based on these characteristics, the best four developed molecules and Zanamivir were submitted to a molecular dynamics simulation investigation to estimate their dynamics within the neuraminidase receptor using Gromacs software. All MD simulation findings show that the generated complexes are very stable when compared to the clinical inhibitor (Zanamivir). In addition, the four designed neuraminidase inhibitors formed very stable complexes with neuraminidase receptor (with total binding energies ranging from -83.50 to -107.85 Kj/mol) according to the total binding energy calculated by MM-PBSA. For the objective of developing new influenza medications, these novel molecules have the potential to be further evaluated <i>in vitro</i> and <i>in vivo</i> for influenza drug discovery.Communicated by Ramaswamy H. Sarma.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":null,"pages":null},"PeriodicalIF":2.7000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Discovery of novel potent drugs for influenza by inhibiting the vital function of neuraminidase via fragment-based drug design (FBDD) and molecular dynamics simulation strategies.\",\"authors\":\"Lotfi Bourougaa, Mebarka Ouassaf, Amneh Shtaiwi\",\"doi\":\"10.1080/07391102.2023.2251065\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The current work describes a fragment linking methodology to generate new neuraminidase inhibitors. A total number of 28,977 fragments from Zinc 20 have been obtained and screened for neuraminidase receptor affinity. Using Schrödinger software, the highest-scoring 270 fragment hits (with scores greater than -7.6) were subjected to fragment combining to create 100 new molecules. These 100 novel compounds were studied using XP docking to evaluate the molecular interaction modes and their binding affinity to neuraminidase receptor. The top ten molecules were selected, for ADMET, drug-likeness features. Based on these characteristics, the best four developed molecules and Zanamivir were submitted to a molecular dynamics simulation investigation to estimate their dynamics within the neuraminidase receptor using Gromacs software. All MD simulation findings show that the generated complexes are very stable when compared to the clinical inhibitor (Zanamivir). In addition, the four designed neuraminidase inhibitors formed very stable complexes with neuraminidase receptor (with total binding energies ranging from -83.50 to -107.85 Kj/mol) according to the total binding energy calculated by MM-PBSA. For the objective of developing new influenza medications, these novel molecules have the potential to be further evaluated <i>in vitro</i> and <i>in vivo</i> for influenza drug discovery.Communicated by Ramaswamy H. Sarma.</p>\",\"PeriodicalId\":15272,\"journal\":{\"name\":\"Journal of Biomolecular Structure & Dynamics\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.7000,\"publicationDate\":\"2024-11-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Biomolecular Structure & Dynamics\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1080/07391102.2023.2251065\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2023/8/28 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Biomolecular Structure & Dynamics","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1080/07391102.2023.2251065","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/8/28 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
目前的工作描述了一种片段连接方法来产生新的神经氨酸酶抑制剂。从锌20中共获得28,977个片段,并进行了神经氨酸酶受体亲和力筛选。使用Schrödinger软件,得分最高的270个片段(得分大于-7.6)进行片段结合,产生100个新分子。利用XP对接技术对这100个新化合物进行了分子相互作用模式及与神经氨酸酶受体的结合亲和力的研究。根据ADMET与药物相似的特征,选择前10个分子。基于这些特征,将最佳的4个开发分子和扎那米韦提交给分子动力学模拟研究,使用Gromacs软件估计它们在神经氨酸酶受体内的动力学。所有MD模拟结果表明,与临床抑制剂(扎那米韦)相比,生成的复合物非常稳定。此外,根据MM-PBSA计算的总结合能,所设计的4种神经氨酸酶抑制剂与神经氨酸酶受体形成了非常稳定的复合物(总结合能在-83.50 ~ -107.85 Kj/mol之间)。为了开发新的流感药物,这些新分子有可能在体外和体内进一步评估,用于流感药物的发现。由Ramaswamy H. Sarma传达。
Discovery of novel potent drugs for influenza by inhibiting the vital function of neuraminidase via fragment-based drug design (FBDD) and molecular dynamics simulation strategies.
The current work describes a fragment linking methodology to generate new neuraminidase inhibitors. A total number of 28,977 fragments from Zinc 20 have been obtained and screened for neuraminidase receptor affinity. Using Schrödinger software, the highest-scoring 270 fragment hits (with scores greater than -7.6) were subjected to fragment combining to create 100 new molecules. These 100 novel compounds were studied using XP docking to evaluate the molecular interaction modes and their binding affinity to neuraminidase receptor. The top ten molecules were selected, for ADMET, drug-likeness features. Based on these characteristics, the best four developed molecules and Zanamivir were submitted to a molecular dynamics simulation investigation to estimate their dynamics within the neuraminidase receptor using Gromacs software. All MD simulation findings show that the generated complexes are very stable when compared to the clinical inhibitor (Zanamivir). In addition, the four designed neuraminidase inhibitors formed very stable complexes with neuraminidase receptor (with total binding energies ranging from -83.50 to -107.85 Kj/mol) according to the total binding energy calculated by MM-PBSA. For the objective of developing new influenza medications, these novel molecules have the potential to be further evaluated in vitro and in vivo for influenza drug discovery.Communicated by Ramaswamy H. Sarma.
期刊介绍:
The Journal of Biomolecular Structure and Dynamics welcomes manuscripts on biological structure, dynamics, interactions and expression. The Journal is one of the leading publications in high end computational science, atomic structural biology, bioinformatics, virtual drug design, genomics and biological networks.