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。

IF 2.7 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Vishakha Chaudhary, Shubhra Chaturvedi, Anju Wadhwa, Presenjit Verma, Divya Gautam, Deepika Sharma, Aastha Garg, Vishal Singh, Rupesh Kumar, Anil K Mishra
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引用次数: 0

摘要

由于生物化学研究已经证明在高度增殖的肿瘤细胞中存在这种受体,sigma-2受体作为一种有希望的癌症诊断和治疗靶点受到了关注。计算药物设计可以帮助创建针对sigma-2的靶向配体,但需要三维受体结构作为输入。本研究旨在建立人类sigma-2受体的同源性模型。将模板蛋白牛sigma-2 (7m93)与查询序列(Q5BJF2)比对,得到5个模型。利用势能参数和分子动力学对这些模型进行筛选,并利用立体化学参数验证了具有最低能量和最大稳定性的模型。该模型在Ramachandran样地允许区域的残差为95.9%,总体质量因子为87.2611%。采用对接评分与pKi文献值的相关分析(R2= 0.744)对模型进行检验。此外,该模型还用于了解新兴的选择性6,7-二甲氧基-1,2,3,4-四氢异喹啉支架衍生物的结合模式,用于设计配体。对该模型和配体结合模型进行了100 ns的分子动力学研究,以研究配合物的稳定性,并与已知拮抗剂sigma 2的相互作用进行了比较。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.

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来源期刊
Journal of Biomolecular Structure & Dynamics
Journal of Biomolecular Structure & Dynamics 生物-生化与分子生物学
CiteScore
8.90
自引率
9.10%
发文量
597
审稿时长
2 months
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.
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