In Silico Exploration of PTP1B Inhibitor from Indole Alkaloids of Rauvolfia serpentina (L.) Benth, a Potent Therapeutic Drug Target for Type 2 Diabetes Mellitus

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.