Cheminformatics identification of modulators of key carbohydrate metabolizing enzymes from Crescentia cujete towards interventive T2DM therapy

Abstract

The therapeutic use of oral hypoglycaemic agents in the effective management of type-2 diabetes mellitus are without adverse effects; thus, calls for alternative and novel candidates from natural products in medicinal plant. The study explored computational approach (molecular docking and molecular dynamics simulation) in the determination of antidiabetic effect of probable candidates from the Crescentia cujete secondary metabolites. The molecular docking results identified the best 5 compounds for each target of diabetes enzymes (alpha-glucosidase, dipeptidyl peptidase-IV, aldose reductase and protein tyrosine phosphatase-1B) where all these compounds (except against PTP-1B) depicted higher docking scores greater than the respective standards (acarbose, Diprotin A, ranirestat) and were further subject to molecular dynamics simulation (MDS) over a period of 100 ns. The results similarly revealed some of the compounds such as benzoic acid and phytol (− 48.414, − 45.112 kcal/mol respectively) as well as chlorogenic acid (− 42.978 kcal/mol) and naringenin (− 31.292 kcal/mol) produced higher binding energy affinities better the standards [acarbose (− 28.248 kcal/mol), ranirestat (− 21.042 kcal/mol)] against alpha-glucosidase and aldose reductase respectively (and vice versa for DPP-IV and PTP-1B) though, these results were inconsistent with findings from the post-dynamics simulation metrics. While isoflavone (alpha-glucosidase), xycaine (DPP-IV), luteolin (aldose reductase) and chlorogenic acid (PTP-1B) were affirmed as best inhibitors of respective enzyme targets, luteolin and chlorogenic acid may be suggested and proposed as probable candidates against type-2 diabetes mellitus and related retinopathy complication based on their affinity for 3 (DPP-IV, aldose reductase and PTP-1B) out of the 4 targets. Further studies are warranted in vitro and in vivo on the antihyperglycaemic effects of these candidates.