Vinutha Kuchana, Vaeshnavi Kashetti, Sai Kiran Reddy Peddi, Sreekanth Sivan, Vijjulatha Manga
{"title":"新型嘌呤基吡啶衍生物B-Raf激酶抑制剂的集成计算机设计方法。","authors":"Vinutha Kuchana, Vaeshnavi Kashetti, Sai Kiran Reddy Peddi, Sreekanth Sivan, Vijjulatha Manga","doi":"10.1080/10799893.2021.1999472","DOIUrl":null,"url":null,"abstract":"<p><p>B-Raf is one among the most frequently mutating proto-oncogene which is associated with the serine/threonine Raf kinase family involved in the RAS-RAF-MEK-ERK pathway, which is the most deregulated pathway in human cancers. Mutant B-Raf <sup>V600E</sup> got an excellent scope for investigation in cancer as a potential therapeutic target. Formerly B-Raf<sup>V600E</sup> is considered the molecular target for numerous antitumor compounds like purinyl pyridine and pyrimidine derivatives. In the current research work using molecular docking approach of Schrodinger Glide 5.6 version, ligand docking, pharmacophore-based virtual screening, binding free energy calculations of a series of 2-amino purinyl pyridine and pyrimidine derivatives were modeled, their docking values were predicted, that were considered to be potent against B-Raf <sup>V600E</sup>. A five-point hypothesis accompanied by a hydrogen bond acceptor(A), two hydrogen bond donors(D), and two aromatic rings (R) was built with a justifiable R<sup>2</sup> value of 0.91 and a Q<sup>2</sup> value of 0.64. Then by using Asinex Elite Synergy database, virtual screening was performed, and identified several potential hits. Subsequently, the molecules which had interactions with the target B-Raf kinase were determined by subjecting the obtained hits for SP and XP docking processes. Finally, for the top leads obtained, binding free energies were accomplished. About 16 new purinyl pyridine molecules were also designed. Almost nine molecules manifested crucial ligand interactions and binding free energies. At the outset, this research paved the way for us in spotting new molecules with B-Raf inhibitory activity, which can further be explored to design molecules with enhanced pharmacokinetic profiles.</p>","PeriodicalId":16962,"journal":{"name":"Journal of Receptors and Signal Transduction","volume":null,"pages":null},"PeriodicalIF":2.6000,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"2","resultStr":"{\"title\":\"Integrated computational approach for <i>in silico</i> design of new purinyl pyridine derivatives as B-Raf kinase inhibitors.\",\"authors\":\"Vinutha Kuchana, Vaeshnavi Kashetti, Sai Kiran Reddy Peddi, Sreekanth Sivan, Vijjulatha Manga\",\"doi\":\"10.1080/10799893.2021.1999472\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>B-Raf is one among the most frequently mutating proto-oncogene which is associated with the serine/threonine Raf kinase family involved in the RAS-RAF-MEK-ERK pathway, which is the most deregulated pathway in human cancers. Mutant B-Raf <sup>V600E</sup> got an excellent scope for investigation in cancer as a potential therapeutic target. Formerly B-Raf<sup>V600E</sup> is considered the molecular target for numerous antitumor compounds like purinyl pyridine and pyrimidine derivatives. In the current research work using molecular docking approach of Schrodinger Glide 5.6 version, ligand docking, pharmacophore-based virtual screening, binding free energy calculations of a series of 2-amino purinyl pyridine and pyrimidine derivatives were modeled, their docking values were predicted, that were considered to be potent against B-Raf <sup>V600E</sup>. A five-point hypothesis accompanied by a hydrogen bond acceptor(A), two hydrogen bond donors(D), and two aromatic rings (R) was built with a justifiable R<sup>2</sup> value of 0.91 and a Q<sup>2</sup> value of 0.64. Then by using Asinex Elite Synergy database, virtual screening was performed, and identified several potential hits. Subsequently, the molecules which had interactions with the target B-Raf kinase were determined by subjecting the obtained hits for SP and XP docking processes. Finally, for the top leads obtained, binding free energies were accomplished. About 16 new purinyl pyridine molecules were also designed. Almost nine molecules manifested crucial ligand interactions and binding free energies. At the outset, this research paved the way for us in spotting new molecules with B-Raf inhibitory activity, which can further be explored to design molecules with enhanced pharmacokinetic profiles.</p>\",\"PeriodicalId\":16962,\"journal\":{\"name\":\"Journal of Receptors and Signal Transduction\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.6000,\"publicationDate\":\"2022-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"2\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Receptors and Signal Transduction\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1080/10799893.2021.1999472\",\"RegionNum\":4,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2021/11/29 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Receptors and Signal Transduction","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1080/10799893.2021.1999472","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2021/11/29 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Integrated computational approach for in silico design of new purinyl pyridine derivatives as B-Raf kinase inhibitors.
B-Raf is one among the most frequently mutating proto-oncogene which is associated with the serine/threonine Raf kinase family involved in the RAS-RAF-MEK-ERK pathway, which is the most deregulated pathway in human cancers. Mutant B-Raf V600E got an excellent scope for investigation in cancer as a potential therapeutic target. Formerly B-RafV600E is considered the molecular target for numerous antitumor compounds like purinyl pyridine and pyrimidine derivatives. In the current research work using molecular docking approach of Schrodinger Glide 5.6 version, ligand docking, pharmacophore-based virtual screening, binding free energy calculations of a series of 2-amino purinyl pyridine and pyrimidine derivatives were modeled, their docking values were predicted, that were considered to be potent against B-Raf V600E. A five-point hypothesis accompanied by a hydrogen bond acceptor(A), two hydrogen bond donors(D), and two aromatic rings (R) was built with a justifiable R2 value of 0.91 and a Q2 value of 0.64. Then by using Asinex Elite Synergy database, virtual screening was performed, and identified several potential hits. Subsequently, the molecules which had interactions with the target B-Raf kinase were determined by subjecting the obtained hits for SP and XP docking processes. Finally, for the top leads obtained, binding free energies were accomplished. About 16 new purinyl pyridine molecules were also designed. Almost nine molecules manifested crucial ligand interactions and binding free energies. At the outset, this research paved the way for us in spotting new molecules with B-Raf inhibitory activity, which can further be explored to design molecules with enhanced pharmacokinetic profiles.
期刊介绍:
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