Abstract:
The increasing incidence of hypercholesterolemia-related
diseases even in the presence of the currently available cholesterol-lowering
drugs indicates a need to discover new therapeutic drugs. This study aimed to
investigate the hypocholesterolemic potential of two triterpenoids isolated from
Protorhus longifolia stem bark. In silico techniques and in vitro enzyme assays
were used to evaluate the potential inhibition of cholesterol esterase and HMGCoA
reductase by the triterpenoids (ARM-2 and RA-5). The toxicity,
modulation of low-density lipoprotein (LDL) uptake, and associated gene
expression were determined in HepG2 hepatocytes. In silico molecular docking
revealed that ARM-2 compared with RA-5 has a relatively stronger binding
affinity for both enzymes. Both triterpenoids further demonstrated promising in
silico drug-likeness properties and favorable ADMET profiles characterized by
high intestinal absorption and lack of CYP450 enzyme inhibition. The
compounds further showed, to varying degrees of efficacy, inhibition of
cholesterol micellization as well as both cholesterol esterase and HMG-CoA reductase activities with IC50 values ranging from 16.4
to 41.1 μM. Moreover, enhanced hepatic cellular LDL uptake and the associated upregulation of the LDL-R and SREBP-2 gene
expression were observed in the triterpenoid-treated HepG2 cells. It is evident that the triterpenoids, especially ARM-2, possess
hypocholesterolemic properties, and these molecules can serve as leads or structural templates for the development of new
hypocholesterolemic drugs.
