Abstract

G Protein-Coupled Receptor gains more importance in cancer research; because of their key role in several physiologic functions of cells. However, most of the GPCR’s are orphan receptors, this hampers the finding of drugs against GPCR. G Protein-Coupled Receptor 116 is an adhesion orphan receptor that intensifies the invasion of cells in Triple-Negative Breast Cancer. In this study, existing FDA approved anticancer drugs were chosen as ligands and molecular docking was performed using in silico protein model of GPR116. Molecular interaction was analyzed carefully to identify the crucial amino acids present in binding pocket. Molecular dynamics simulations study executed to verify the structural and dynamic properties of Doxorubicin–GPR116 protein complex. The results have shown that Doxorubicin, Neratinib maleate, Epirubicin, and Lapatinib Ditosylate have good interaction with GPR116 binding site. Tyrosine 195 (Y195), Cysteine 196 (C196), Argenine 197 (R197), and Tryptophan 100 (W100) are commonly found in the majority of ligand–target interaction, hence based on the computational studies selective amino acids might be crucial for functional properties. Further to confirm crucial amino acids, computational mutation studies were executed. Molecular docking analysis with mutated GPR116 disclosed that significant variation in G score compared withligand–native protein interaction. Hence, the theoretical confirmatory structural properties changes support to prove selective crucial amino acids play the significant role in ligand binding. Molecular dynamic simulation results reveal that the interaction was stable throughout the MD simulation. To the best of our prognosis, GPR116 could be the best molecular target for breast cancer drug discovery.

Communicated by Ramaswamy H. Sarma

摘要

G 蛋白偶联受体在癌症研究中越来越重要；因为它们在细胞的几种生理功能中起着关键作用。然而，大多数 GPCR 是孤儿受体，这阻碍了针对 GPCR 的药物的发现。G 蛋白偶联受体 116 是一种粘附孤儿受体，可加强三阴性乳腺癌细胞的侵袭。在本研究中，选择现有的 FDA 批准的抗癌药物作为配体，并使用in silico进行分子对接。GPR116 的蛋白质模型。仔细分析分子相互作用以鉴定结合口袋中存在的关键氨基酸。执行分子动力学模拟研究以验证多柔比星-GPR116 蛋白质复合物的结构和动态特性。结果表明，多柔比星、马来酸来那替尼、表柔比星和二甲苯磺酸拉帕替尼与GPR116结合位点具有良好的相互作用。酪氨酸 195 (Y195)、半胱氨酸 196 (C196)、精氨酸 197 (R197) 和色氨酸 100 (W100) 常见于大多数配体-靶标相互作用中，因此基于计算研究，选择性氨基酸可能对功能性至关重要特性。为了进一步确认关键氨基酸，进行了计算突变研究。用突变的 GPR116 进行的分子对接分析揭示了G评分与配体-天然蛋白质相互作用进行比较。因此，理论验证性结构特性的变化支持证明选择性关键氨基酸在配体结合中发挥重要作用。分子动力学模拟结果表明，在整个 MD 模拟过程中，相互作用是稳定的。就我们的预后而言，GPR116 可能是乳腺癌药物发现的最佳分子靶点。

由 Ramaswamy H. Sarma 交流