Department of Animal and Biomedical Sciences, School of Life Sciences, Lanzhou University, 222 Tianshui South Road, Lanzhou 730000, China.
Department of Animal and Biomedical Sciences, School of Life Sciences, Lanzhou University, 222 Tianshui South Road, Lanzhou 730000, China,; Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou University, 222 Tianshui South Road, Lanzhou 730000, China.
Int J Biol Macromol. 2024 Aug;275(Pt 2):133710. doi: 10.1016/j.ijbiomac.2024.133710. Epub 2024 Jul 6.
Delta-opioid receptor protein (OPRD1) is one of the potential targets for treating pain. The presently available opioid agonists are known to cause unnecessary side effects. To discover a novel opioid agonist, our research group has synthesized a chimeric peptide MCRT and proved its potential activity through in vivo analysis. Non-synonymous SNPs (nsSNPs) missense mutations affect the functionality and stability of proteins leading to diseases. The current research was focused on understanding the role of MCRT in restoring the binding tendency of OPRD1 nsSNPs missense mutations on dynamic nature in comparison with Deltorphin-II and morphiceptin. The deleterious effects of nsSNPs were analyzed using various bioinformatics tools for predicting structural, functional, and oncogenic influence. The shortlisted nine nsSNPs were predicted for allergic reactions, domain changes, post-translation modification, multiple sequence alignment, secondary structure, molecular dynamic simulation (MDS), and peptide docking influence. Further, the docked complex of three shortlisted deleterious nsSNPs was analyzed using an MDS study, and the highly deleterious shortlisted nsSNP A149T was further analyzed for higher trajectory analysis. MCRT restored the binding tendency influence caused by nsSNPs on the dynamics of stability, functionality, binding affinity, secondary structure, residues connection, motion, and folding of OPRD1 protein.
德尔塔阿片受体蛋白（OPRD1）是治疗疼痛的潜在靶点之一。目前可用的阿片类激动剂已知会引起不必要的副作用。为了发现一种新型的阿片类激动剂，我们的研究小组合成了一种嵌合肽 MCRT，并通过体内分析证明了其潜在的活性。非同义单核苷酸多态性（nsSNP）错义突变会影响蛋白质的功能和稳定性，从而导致疾病。目前的研究集中在了解 MCRT 在恢复 OPRD1 nsSNP 错义突变对动态结合倾向方面的作用，与 Deltorphin-II 和吗啡肽相比。使用各种生物信息学工具分析 nsSNP 的有害影响，以预测结构、功能和致癌影响。对 9 个 nsSNP 进行了过敏反应、结构域变化、翻译后修饰、多序列比对、二级结构、分子动力学模拟（MDS）和肽对接影响的预测。此外，对三个选定的有害 nsSNP 的对接复合物进行了 MDS 研究分析，对高度有害的选定 nsSNP A149T 进行了进一步的轨迹分析。MCRT 恢复了 nsSNP 对 OPRD1 蛋白稳定性、功能、结合亲和力、二级结构、残基连接、运动和折叠动力学的影响。
