Abstract

Protein tyrosine phosphatase 1B (PTP1B) is implicated as a key negative regulator of the insulin. Plant derived PTP1B inhibitors have emerged as attractive and potent therapeutic agents for the treatment of Type 2 diabetes mellitus (T2DM) and obesity. Rauvolfia serpentina is widely used in Indian Ayurvedic Medical System for the treatment of diabetes. We investigated whether the indole alkaloids of R. serpentina suppress the activity of PTPIB. The structures of 25 indole alkaloids of R. serpentina were obtained from NCBI pubchem and KNApSAcK PRIMe database. The crystal structure of protein PTPIB was retrieved from PDB. The interaction between indole alkaloids and PTP 1B was analyzed using reverse pharmacophore mapping by pharmMapper server. STRING database was applied to find out the association of drug target with other protein. The oral bioavailablity and toxicity profiles were verified by Osiris property explorer, Lazar and admetSAR tools. The prominent metabolic site of indole alkaloides and PTP 1B inhibitor, were predicted using metaprint 2D and autodock tool respectively. Yohimbine exhibited potential binding affinity (ΔG = –5.03 Kcal/mol) against PTP1B. Notably, TYR 46 amino acid residue of PTP 1 B exhibit two π–π stacking interactions with the yohimbine alkaloid in between protein-ligand complex. We proved that the yohimbine is the new lead for design and synthesis of PTP1B inhibitor for the treatment of T2DM.

中文翻译：

---

萝芙木吲哚生物碱中 PTP1B 抑制剂的计算机模拟探索，2 型糖尿病的有效治疗药物靶点

摘要

蛋白酪氨酸磷酸酶 1B (PTP1B) 被认为是胰岛素的关键负调节因子。植物源性 PTP1B 抑制剂已成为治疗 2 型糖尿病 (T2DM) 和肥胖症的有吸引力且有效的治疗剂。蛇形萝芙木在印度阿育吠陀医疗系统中广泛用于治疗糖尿病。我们研究了R. serpentina的吲哚生物碱是否抑制 PTPIB 的活性。从 NCBI pubchem 和 KNApSAcK PRIMe 数据库中获得了25 种蛇纹草吲哚生物碱的结构。从 PDB 中检索蛋白质 PTPIB 的晶体结构。通过 pharmMapper 服务器使用反向药效团作图分析吲哚生物碱和 PTP 1B 之间的相互作用。应用STRING数据库来找出药物靶点与其他蛋白质的关联。口服生物利用度和毒性特征通过 Osiris property explorer、Lazar 和 admetSAR 工具进行了验证。分别使用metaprint 2D和autodock 工具预测吲哚生物碱和PTP 1B 抑制剂的主要代谢位点。育亨宾对 PTP1B 表现出潜在的结合亲和力 (Δ G = –5.03 Kcal/mol)。值得注意的是，PTP 1 B 的 TYR 46 氨基酸残基在蛋白质-配体复合物之间与育亨宾生物碱表现出两种 π-π 堆积相互作用。我们证明育亨宾是设计和合成治疗 T2DM 的 PTP1B 抑制剂的新先导物。