{"title":"6,7-二甲氧基-1,2,3,4-四氢异喹啉衍生物作为sigma-2受体配体的同源性建模、分子对接和MD模拟研究。","authors":"Vishakha Chaudhary, Shubhra Chaturvedi, Anju Wadhwa, Presenjit Verma, Divya Gautam, Deepika Sharma, Aastha Garg, Vishal Singh, Rupesh Kumar, Anil K Mishra","doi":"10.1080/07391102.2025.2480273","DOIUrl":null,"url":null,"abstract":"<p><p>The sigma-2 receptor has gathered attention as a promising target for cancer diagnosis and therapy since biochemical studies have evidenced the presence of the receptor in highly proliferating tumor cells. Computational drug design can help create targeted ligands against sigma-2, but a three-dimensional receptor structure is required as input. This study aims to develop a homology model of the human sigma-2 receptor. The template protein bovine sigma-2 (7m93) was aligned with the query sequence (Q5BJF2) to generate five models. These models were screened using potential energy parameters and molecular dynamics, with the model having the lowest energy and maximum stability being validated using stereo chemical parameters. The accepted model had 95.9% residues in allowed regions of the Ramachandran plot and an overall quality factor of 87.2611%. The model was tested using correlation analysis (<i>R</i><sup>2</sup>= 0.744) of docking score and literature values of pKi. In addition, the model is used to understand the binding pattern of emerging selective 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline scaffold-based derivatives for designing ligands. The molecular dynamics studies of the model and ligand-bound model were performed for 100 ns to study the stability of the complexes, and the interactions compared with the known antagonist of sigma 2.</p>","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-15"},"PeriodicalIF":2.7000,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Homology modeling, molecular docking and MD simulations study of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as sigma-2 receptor ligands.\",\"authors\":\"Vishakha Chaudhary, Shubhra Chaturvedi, Anju Wadhwa, Presenjit Verma, Divya Gautam, Deepika Sharma, Aastha Garg, Vishal Singh, Rupesh Kumar, Anil K Mishra\",\"doi\":\"10.1080/07391102.2025.2480273\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The sigma-2 receptor has gathered attention as a promising target for cancer diagnosis and therapy since biochemical studies have evidenced the presence of the receptor in highly proliferating tumor cells. Computational drug design can help create targeted ligands against sigma-2, but a three-dimensional receptor structure is required as input. This study aims to develop a homology model of the human sigma-2 receptor. The template protein bovine sigma-2 (7m93) was aligned with the query sequence (Q5BJF2) to generate five models. These models were screened using potential energy parameters and molecular dynamics, with the model having the lowest energy and maximum stability being validated using stereo chemical parameters. The accepted model had 95.9% residues in allowed regions of the Ramachandran plot and an overall quality factor of 87.2611%. The model was tested using correlation analysis (<i>R</i><sup>2</sup>= 0.744) of docking score and literature values of pKi. In addition, the model is used to understand the binding pattern of emerging selective 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline scaffold-based derivatives for designing ligands. The molecular dynamics studies of the model and ligand-bound model were performed for 100 ns to study the stability of the complexes, and the interactions compared with the known antagonist of sigma 2.</p>\",\"PeriodicalId\":15272,\"journal\":{\"name\":\"Journal of Biomolecular Structure & Dynamics\",\"volume\":\" \",\"pages\":\"1-15\"},\"PeriodicalIF\":2.7000,\"publicationDate\":\"2025-04-07\",\"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/10.1080/07391102.2025.2480273\",\"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 Biomolecular Structure & Dynamics","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1080/07391102.2025.2480273","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}
Homology modeling, molecular docking and MD simulations study of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as sigma-2 receptor ligands.
The sigma-2 receptor has gathered attention as a promising target for cancer diagnosis and therapy since biochemical studies have evidenced the presence of the receptor in highly proliferating tumor cells. Computational drug design can help create targeted ligands against sigma-2, but a three-dimensional receptor structure is required as input. This study aims to develop a homology model of the human sigma-2 receptor. The template protein bovine sigma-2 (7m93) was aligned with the query sequence (Q5BJF2) to generate five models. These models were screened using potential energy parameters and molecular dynamics, with the model having the lowest energy and maximum stability being validated using stereo chemical parameters. The accepted model had 95.9% residues in allowed regions of the Ramachandran plot and an overall quality factor of 87.2611%. The model was tested using correlation analysis (R2= 0.744) of docking score and literature values of pKi. In addition, the model is used to understand the binding pattern of emerging selective 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline scaffold-based derivatives for designing ligands. The molecular dynamics studies of the model and ligand-bound model were performed for 100 ns to study the stability of the complexes, and the interactions compared with the known antagonist of sigma 2.
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.