In vitro and in silico analysis proving DPP4 inhibition and diabetes-associated gene network modulation by a polyherbal formulation: Nisakathakadi Kashaya

Abstract

Dipeptidyl-peptidase IV (DPP4) inhibitors are an important class of anti-diabetic drugs recognised for their systemic biological actions. Polyherbal preparations like Ayurveda formulations are considered to be ideal sources for discovering novel DPP4 inhibitors owing to their rich phytochemical composition. The current study reports the DPP4 inhibitory potential of a clinically established Ayurvedic anti-diabetic formulation Nisakathakadi Kashaya (NK) using in vitro assay and substantiates it by identifying potential bioactives responsible for DPP4 inhibition using computational biology tools. NK showed a dose-dependent DPP4 inhibition with an IC₅₀ of 2.06 μg GAE/mL, and the molecular docking and simulation studies showed three compounds, namely Terchebin, Locaracemoside B and 1,2,4,6 Tetra o Galloyl Beta D Glucose having stable interactions with DPP4 similar to the standard drug Vildagliptin. Further, for the reason that polyherbal formulations exert a network pharmacology mode of action, in silico analysis was carried out to identify the other putative phytochemical-protein networks modulated by NK. The complex pharmacological network of the formulation was explored further using a subnetwork of diabetes proteins and their relationship with diabetes-associated comorbidities. A number of key targets like TNFα, TGFβ1, SOD1, SOD2, AKT1, DPP4 and GLP1R were identified in the protein-protein interaction network that is vital to diabetic progression and complications. A combination of in vitro and in silico methods allowed us to prove the DPP4 inhibition potential of NK as well as provided insights into the possible pharmacological networking through which NK potentially exerts its systemic effect in diabetes management.Communicated by Ramaswamy H. Sarma.

Keywords: ayurveda; diabetes; docking; dpp4; molecular dynamics; network pharmacology.