Bioprospection for Putative Antidiabetic Leads from Momordica balsamina Using Network Pharmacology, Molecular Modelling and Density Functional Theory Calculations

Abstract

With the increasing incidence and mortality rate of type 2 diabetes mellitus (T2DM), alternative management options with better efficacy and less adverse effects are continuously being researched. Despite reports validating the antidiabetic property of Momordica balsamina, computational bioprospection for its putative antidiabetic leads and mechanism of action remain elusive. The study employed network pharmacology, molecular docking, molecular dynamics simulation, density functional theory, and in silico pharmacokinetics prediction to identify the putative leads and discern the antidiabetic mechanism of action M. balsamina. An initial screening of the 74 compounds retrieved from M. balsamina showed oral drug-likeness while gene ontology analysis identified EGFR tyrosinase kinase inhibitor as the most significant pathway with IGF1R and GSK3B being the most prominent genes in the pathway. Analysis of the binding interactions of the top-ranked compounds and the genes revealed that except for myricetin-GSK3B complex, other resulting complexes had lower binding free energy values for the genes relative to the standard gene inhibitors. Kaempferol-3-O-glucoside (-51.50 ± 7.97 kcal/mol) and balsaminoside B (-61.79 ± 7.35 kcal/mol), however, presented superior binding affinities with IGF1R and GSK3B, respectively, suggestive of their better potential to interact and downregulate the genes than other top M. balsamina compounds. Evidence from this study is the potential of M. balsamina compounds to downregulate IGF1R and GSK3B expressions and formation of thermodynamically stable and compact interactions with the genes for glucose homeostasis via insulin sensitivity and glycogen metabolism regulation. Thus, the identified leads can be further explored as possible candidates for antidiabetic drug development.