Alkaloid Fraction of Litsea glutinosa Leaves Provides an Important Precursor for Inhibition of Dipeptidyl Peptidase 4 Activity

Abstract

Abstract Dipeptidyl Peptidase-4 (DPP-4) is a serine protease that plays an important role in metabolic and immunological functions. DPP-4 inhibitor is an alternative oral drug for the therapy of patients with Type 2 Diabetes Mellitus who do not respond to the standard therapy (metformin). However, long term uses of this drug remain unknown. Therefore, this study aimed to identify a phytochemical that could inhibit the DPP-4 and to extract it. This biocomputational study used a molecular docking method. Three-dimensional structure of DPP-4 and sitagliptin was downloaded from Protein Data Bank with access code PDB 3F8S and ZINC database with access code ZINC22007143. Indonesian phytochemicals were selected as research samples, which had 3 D structure and met the criteria of Lipinski. Leaves of L. glutinosa were extracted using the soxhletation method with ethanol solvent of which alkaloid fraction was generated with phosphoric acid, n-hexane and chloroform solvents. Boldine concentration in extract and alkaloid fraction of L. glutinosa leaves was quantified using the High Performance Liquid Chromatography device. Actinodaphnine interacted with the catalytic triad of DPP4 (Ser 630 and His 740) and had three additional residues to bind to DPP-4 as same as sitagliptin (Glu 205, Glu 206 and Tyr 662). Naturally, actinodaphnine was synthesized from boldine. Total boldine concentration in L. glutinosaextract and alkaloid fraction were 1.11 and 2.14 mM respectively. Boldine as the precursor of actinodaphnine was successfully isolated from L. glutinosa leaves and will become a promising phytochemical for drug development of DPP-4 inhibitor.